A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Upadacitnib (ABT-494) for Induction and Maintenance Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the
large intestine characterized by inflammation and ulceration of mainly the
mucosal and occasionally submucosal intestinal layers. The hallmark clinical
symptoms include bloody diarrhea associated with rectal urgency and tenesmus.
The most severe intestinal manifestations of UC are toxic megacolon and
perforation. Patients with UC are at an increased risk for colon cancer, and
the risk increases with the duration of disease as well as extent of colon
affected by the disease.

The aim of medical treatment in UC is to control inflammation and reduce
symptoms. Available pharmaceutical therapies are limited, do not always
completely abate the inflammatory process, and may have significant adverse
effects. Therapies for mild to moderate active UC include 5-aminosalicylic acid
derivatives and immunosuppressants. Corticosteroids are used in patients with
more severe symptoms but are not useful for longer term therapy. The frequency
and severity of corticosteroid toxicities are significant, including
infections, emotional and psychiatric disturbances, skin injury, and metabolic
bone disease. Patients with moderate to severe symptoms may derive some
benefits from immunomodulatory agents, however, the use of these agents is
limited as induction treatment due to a slow onset of action (3 to 6 months)
and as maintenance therapy due to adverse events (AEs), including bone marrow
suppression, infections, hepatotoxicity, pancreatitis, and malignancies.

Biological agents targeting specific immunological pathways have been evaluated
for their therapeutic effect in treating patients with UC as well, such as
anti-tumor necrosis factor (TNF) agents. Anti-TNF therapies are an effective
treatment for patients who are steroid refractory or steroid dependent, who had
inadequate response to a thiopurine, or who are intolerant to these
medications. Potential risks with anti-TNF therapies include infusion or
injection site reactions, serious infections, lymphoma, heart failure,
lupus-like syndromes, and demyelinating conditions. Despite the beneficial
results achieved with the available biologic agents, only 17% to 45% of
patients who receive them are able to achieve clinical remission. Thus, there
remains a clear medical need for additional therapeutic options in UC for
patients with inadequate response to or intolerance to conventional therapies
and biologic therapies.

The Janus kinases or JAKs are a family of intracellular tyrosinekinases that
function as dimers in the signaling process of many cytokine receptors. The
JAKs play a critical role in both innate and adaptive immunity, making them
attractive targets for the treatment of inflammatory diseases. Targeting the
Janus activated kinase (JAK) signaling pathway for autoimmune diseases is
supported by the involvement of various pro-inflammatory cytokines that signal
via JAK pathways in the pathogenesis of these immune-related disorders.
Upadacitinib is a novel selective JAK1 inhibitor. JAK1 inhibition blocks the
signaling of many important pro-inflammatory cytokines.

Main objective of SS1 (Ph2b induction) is to characterize dose-response,
efficacy, and safety of upadacitinib compared to placebo in inducing clinical
remission defined by Adapted Mayo score in subjects with moderately to severely
active ulcerative colitis (UC) in order to identify the induction dose of
upadacitinib for further evaluation in Phase 3 studies, SS1 has closed
enrollment and all subjects have completed the induction phase.

Main objective of SS2 (Ph3 induction) is to evaluate efficacy and safety of
upadacitinib 45 mg once daily (QD) compared to placebo in inducing clinical
remission in subjects with moderately to severely active UC.

Main objective of SS3 (Ph3 maintenance) is to evaluate efficacy and safety of
upadacitinib 15 mg QD and 30 mg QD compared to placebo in achieving clinical
remission in subjects with moderately to severely active UC who achieved
clinical response following induction with upadacitinib in
M14-234 SS1 or 2 or M14-675.

This is a Phase 2b/3, multicenter, randomized, double-blind, placebo-controlled
study designed to evaluate the efficacy, safety, and pharmacokinetics of
upadacitinib as induction and maintenance therapy in adult subjects with
moderately to severely active UC. The study comprises 3 substudies: a Phase 2b
dose-ranging induction substudy (Substudy 1), a Phase 3 dose-confirming
induction substudy (Substudy 2), and a Phase 3 maintenance substudy (Substudy
3).

All subjects receive upadacitinib or placebo tablets (oral) once a day, until
end of the study or discontinuation.

Upadacitinib 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. upadacitinib was
tested in two studies in patients with RA. upadacitinib was generally
well-tolerated and the types and frequencies of side-effects were typical of
patients treated with traditional RA medications. The most common reported AEs
were: headache, upper chest infection, common cold, back pain, diarrhea, and
cough. Study M14-234, a proposed phase 2b/3 double-blind randomized controlled
study in UC subjects with multiple doses of upadacitinib is based on the
following supportive findings: 1) demonstrated improved potency of
upadacitinib versus tofacitinib in preclinical models of inflammation; 2)
confirmed JAK1 selectivity of upadacitinib 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 in single ascending dose and multiple ascending dose studies in
healthy volunteers; 5) evidence that JAK inhibition in inflammatory bowel
disease results in clinical and endoscopic improvement; and 6) evidence of
efficacy and safety in a different inflammatory disease (rheumatoid arthritis).
The possible clinical improvement outweighs the risks mentioned above as well
as the limited additional study activities over a period of 77 weeks (doctor
visits, blood drawings, questionnaires and medication diary). Additionally,
subjects are closely monitored for any AEs and their relationship to the study
drug will be evaluated by the investigator, documented and analyzed.