TRUE NORTH
Study Design
for ZEPOSIA

TRUE NORTH Study Design for ZEPOSIA

ZEPOSIA was evaluated in 2 multicenter, randomized, double-blind, placebo-controlled clinical studies¹

TRUE NORTH Study Design^1-3

TRUE NORTH is a 2 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active UC

2 multicenter, randomized, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active UC

UC Study 1 (10-week induction): 645 patients were randomized 2:1 to either ZEPOSIA 0.92 mg given orally once daily or placebo for 10 weeks, beginning with a dosage titration. The trial included patients who had an inadequate response or were intolerant to any of the following: oral aminosalicylates, corticosteroids, immunomodulators, or a biologic. Patients were required to be on stable doses of oral aminosalicylates and/or corticosteroids.¹

UC Study 2 (42-week maintenance): 457 patients who received ZEPOSIA in either UC Study 1 or in an open-label arm and achieved clinical response at Week 10 were re-randomized 1:1 and were treated with either ZEPOSIA 0.92 mg (n=230) or placebo (n=227) for 42 weeks (UC Study 2), for a total of 52 weeks of treatment.¹

TRUE NORTH OLE is an ongoing trial that enrolled patients who were nonresponders at the end of induction, experienced disease relapse during maintenance, or completed maintenance treatment in the Phase 3 TRUE NORTH study or remained at study closure and received once-daily oral ZEPOSIA 0.92 mg in the Phase 2 TOUCHSTONE OLE. A total of 823 patients from TRUE NORTH entered the TRUE NORTH OLE.^2,4,5

Endpoints were evaluated at Weeks 46, 94, and 142 of the OLE for all patients who entered the OLE from the TRUE NORTH parent study and for a subset of patients in clinical remission or clinical response at Week 52 and had continuous ZEPOSIA exposure. Endpoints include clinical remission, clinical response, endoscopic improvement, and CS-free remission. Safety was evaluated for all 823 patients who entered the OLE from the TRUE NORTH parent study.^4-7

^aPatients who had a clinical response while they were on placebo at the end of the induction period continued to receive double-blind placebo during the maintenance period and could enter the extension trial at Week 52 or after disease relapse.²
^bResponders are those who achieved clinical response, defined as a reduction from baseline in the 3-component Mayo score of ≥2 and ≥35%, and a reduction from baseline in the RBS of ≥1 or an absolute RBS of 0 or 1.¹

CS=corticosteroid; OLE=open-label extension; RBS=rectal bleeding subscore; UC=ulcerative colitis.

Select Endpoint Definitions¹

Primary Endpoint¹

Clinical Remission

3-component Mayo score consisting of rectal bleeding subscore (RBS)=0, stool frequency subscore (SFS) 0 or 1 (and a decrease of ≥ 1 point from baseline SFS), and endoscopy subscore 0 or 1 without friability

Key Secondary Endpoints¹

Clinical Response

A reduction from baseline in the 3-component Mayo score of ≥2 points and ≥35%, and a reduction from baseline in RBS of ≥1 point or an absolute RBS of 0 or 1

Endoscopic Improvement

Mayo endoscopy subscore of 0 or 1 point without friability

Endoscopic-Histologic Mucosal Improvement

Mayo endoscopy subscore of 0 or 1 without friability and histologic improvement of colonic tissue (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue, ie, Geboes <2.0)

CS-Free Clinical Remission

Clinical remission at Week 52 while off corticosteroids for ≥12 weeks

Key Inclusion Criteria^1,2

Moderately to severely active UC (Mayo score of 6 to 12)

With endoscopy subscore ≥2
With RBS ≥1
With SFS ≥1

An inadequate response or intolerance to any of the following: oral aminosalicylates, corticosteroids, immunomodulators, or a biologic
Patients were required to be on stable doses of oral aminosalicylates and/or corticosteroids (prednisone daily dose up to 20 mg equivalent or budesonide extended-release tablets)

Key Exclusion Criteria^1,3

Clinically relevant cardiovascular conditions or other relevant diseases that could impact the implementation or interpretation of the trial, or put the patient at risk
History of uveitis or macular edema
Concomitant use of biologics or immunomodulators
Pregnant or lactating women

Among the patients considered for the UC studies, 98.8% (2152/2178)
passed protocol-defined preexisting cardiac
disorder screening^8c

^cIncludes UC Study 1 from the TRUE NORTH trial and the phase 2 TOUCHSTONE trial. ZEPOSIA was not studied in patients who had^1,8:

A myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization within the last 6 months
New York Heart Association Class III/IV heart failure
Cardiac conduction or rhythm disorders, including sick sinus syndrome, significant QT prolongation (QTcF >450 msec in males, >470 msec in females), risk factors for QT prolongation, or other conduction abnormalities or cardiac condition that in the opinion of the treating investigator could jeopardize the patient's health
Other preexisting stable cardiac conditions without clearance from a cardiologist
Severe untreated sleep apnea
A resting heart rate less than 55 beats per minute (bpm) at baseline

CS=corticosteroid; QT=an extended interval between the heart contracting and relaxing; QTcF=corrected QT interval by Fridericia; TIA=transient ischemic attack; UC=ulcerative colitis.

UC Study 1 Baseline Characteristics^1,2

Baseline Patient Characteristics^1,2

	Disease Severity
	Male	~60%
	Age	~42 years
	Time Since UC Diagnosis	~7 years
	Total Mayo Score	~9
	Moderate Disease (Mayo Score 6-10)	86%
	Severe Disease (Mayo Score 11-12)	14%
	Concomitant Medication Use
	Mesalamine	71%
	Sulfasalazine	13%
	Oral Corticosteroids	33%
	Prior Medication Use
	TNFi (Previous Failure or Intolerance)	30%
	Of these patients, 47% were exposed to vedolizumab

At entry to UC Study 2 (maintenance),
35% of patients were in clinical remission;
29% of patients were on CS; and 31% of patients
had an inadequate response, loss of response,
or intolerance to TNFi.¹

CS=corticosteroid; TNFi=tumor necrosis factor inhibitor; UC=ulcerative colitis.