14 CLINICAL STUDIES

14.1 Multiple Sclerosis

The efficacy of ZEPOSIA was demonstrated in 2 randomized, double-blind, double-dummy, parallel-group, active comparator-controlled clinical trials of similar design, in patients with relapsing forms of MS [MS Study 1 (NCT02294058) and MS Study 2 (NCT02047734)]. Patients in Study 1 were treated until the last enrolled patient completed 1 year of treatment. Patients in Study 2 were treated for 24 months. Both studies included patients who had experienced at least 1 relapse within the prior year, or 1 relapse within the prior 2 years with evidence of at least a gadolinium-enhancing (GdE) lesion in the prior year, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.0 at baseline. Patients with primary progressive MS were excluded.

Patients were randomized to receive either ZEPOSIA 0.92 mg given orally once daily, beginning with a dosage titration [see Dosage and Administration (2.2)], or interferon (IFN) beta-1a, the active comparator, 30 mcg given intramuscularly once weekly. Neurological evaluations were performed at baseline, every 3 months, and at the time of a suspected relapse. Brain MRI scans were performed at baseline, 6 months (Study 1), 1 year (Studies 1 and 2), and 2 years (Study 2).

The primary endpoint of both Study 1 and Study 2 was the annualized relapse rate (ARR) over the treatment period (Study 1) and 24 months (Study 2). Additional outcome measures included: 1) the number of new or enlarging MRI T2 hyperintense lesions over 12 and 24 months, 2) the number of MRI T1 Gadolinium-enhancing (Gd+) lesions at 12 and 24 months, and 3) the time to confirmed disability progression, defined as at least a 1-point increase from baseline EDSS confirmed after 3 months and after 6 months. Confirmed disability progression was evaluated in a pooled analysis of Studies 1 and 2.

In Study 1, a total of 895 patients were randomized to receive ZEPOSIA (n=447) or IFN beta-1a (n=448); of these patients, 94% who received ZEPOSIA and 92% who received IFN beta-1a completed the study. The mean age was 35.4 years, 99.8% were White, and 65% were female. The mean time since MS symptom-onset was 6.9 years, and the median EDSS score at baseline was 2.5; 31% had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the prior year was 1.3 and 48% of patients had one or more T1 Gd-enhancing lesions (mean 1.8) on their baseline MRI scan.

In Study 2, a total of 874 patients were randomized to receive ZEPOSIA (n=433) or IFN beta-1a (n=441); of these patients, 90% who received ZEPOSIA and 85% who received IFN beta-1a completed the study. The mean age was 35.6 years, 98% were White, and 68% were female. The mean time since MS symptom onset was 6.6 years, and the median EDSS score at baseline was 2.5; 29% of patients had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the prior year was 1.3 and 43% of patients had one or more T1 Gd-enhancing lesions (mean 1.7).

The ARR was statistically significantly lower in patients treated with ZEPOSIA 0.92 mg than in patients who received IFN beta-1a 30 mcg IM. The number of new or enlarging T2 lesions and the number of GdE lesions were statistically significantly lower in patients treated with ZEPOSIA 0.92 mg than in patients who received IFN beta-1a.

There was no statistically significant difference in the three-month and six-month confirmed disability progression between ZEPOSIA and IFN beta-1a-treated patients over 2 years.

The results for Study 1 and Study 2 are shown in Table 8.

Table 8: Clinical and MRI Endpoints from MS Study 1 and Study 2
a Through the treatment period (mean duration 13.6 months). b Over treatment period for Study 1 and over 24 months for Study 2. c Disability progression defined as 1-point increase in Expanded Disability Status Scale (EDSS) confirmed 3 months or 6 months later. d Prospective planned pooled analysis of Studies 1 and 2. e Not statistically significant. f Over 12 months for Study 1 and over 24 months for Study 2. g At 12 months for Study 1 and at 24 months for Study 2.
Endpoints	Study 1		Study 2
	ZEPOSIA 0.92 mg (n=447) %	IFN beta-1a 30 mcg (n=448) %	ZEPOSIA 0.92 mg (n=433) %	IFN beta-1a 30 mcg (n=441) %
Clinical Endpoints
Annualized Relapse Rate (Primary Endpoint)	0.181a	0.350 a	0.172	0.276
Relative Reduction	48% (p<0.0001)		38% (p<0.0001)
Percentage of patients without relapseb	78%	66%	76%	64%
Proportion of Patients with 3-Month Confirmed Disability Progressionc,d	7.6% ZEPOSIA vs. 7.8% IFN beta-1a
Hazard Ratio	0.95 (p=0.77)e
MRI Endpoints
Mean number of new or enlarging T2 hyperintense lesions per MRIf	1.47	2.84	1.84	3.18
Relative Reduction	48% (p<0.0001)		42% (p<0.0001)
Mean number of T1 Gd-enhancing lesionsg	0.16	0.43	0.18	0.37
Relative Reduction	63% (p<0.0001)		53% (p=0.0006)

A similar effect of ZEPOSIA on the ARR compared to IFN beta-1a was observed in exploratory subgroups defined by sex, age, prior non-steroid therapy for MS, and baseline disease activity.

14.2 Ulcerative Colitis

The efficacy and safety of ZEPOSIA were evaluated in two multicenter, randomized, double-blind, placebo-controlled clinical studies [UC Study 1 (induction) and UC Study 2 (maintenance) (NCT02435992)] in adult patients with moderately to severely active ulcerative colitis.

UC Study 1

In UC Study 1, a total of 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 [see Dosage and Administration (2.2)]. The trial included adult patients with moderately to severely active UC who had an inadequate response or were intolerant to any of the following: oral aminosalicylates, corticosteroids, immunomodulators (e.g., 6-mercaptopurine and azathioprine), or a biologic (e.g., TNF blocker and/or vedolizumab). 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) prior to enrollment. Seventy-one percent of patients were receiving mesalamine, 13% sulfasalazine, and 33% oral corticosteroids. A total of 30% of patients had previously failed or were intolerant to TNF blockers. Of these patients, 63% received at least two biologics including TNF blockers.

The disease activity was assessed by the Mayo score (0 to 12) which consists of four subscores (0 to 3 for each subscore): stool frequency, rectal bleeding, findings on centrally-read endoscopy, and physician global assessment. An endoscopy subscore of 2 was defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of 3 was defined by spontaneous bleeding and ulceration. Enrolled patients had Mayo scores between 6 to 12; at baseline, patients had a median Mayo score of 9, with 86% of patients having moderate disease (Mayo score 6-10), and 14% having severe disease (Mayo score 11-12).

Concomitant immunomodulators or biologic therapies were not permitted.

The primary endpoint was clinical remission at Week 10, defined using a 3-component Mayo score without the physician global assessment: rectal bleeding subscore = 0, stool frequency subscore = 0 or 1 (and a decrease of ≥ 1 point from the baseline stool frequency subscore), and endoscopy subscore = 0 or 1 (an endoscopy subscore of 0 defined as normal or inactive disease, and an endoscopy subscore of 1 defined as presence of erythema, decreased vascular pattern and no friability).

The secondary endpoints were clinical response, endoscopic improvement, and endoscopic-histologic mucosal improvement. Clinical response (reduction from baseline in the 3-component Mayo score of ≥ 2 points and ≥ 35%, and a reduction from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1), endoscopic improvement (Mayo endoscopy subscore of 0 or 1), and endoscopic-histologic mucosal improvement [combined endoscopic improvement and histologic improvement of colonic tissue (no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue, i.e., Geboes < 2.0)].

A significantly greater proportion of patients treated with ZEPOSIA achieved clinical remission, clinical response, endoscopic improvement, and endoscopic-histologic mucosal improvement compared to placebo at Week 10 (see Table 9).

Table 9: Proportion of Patients Meeting Efficacy Endpoints in the Induction Period at Week 10 in UC Study 1
CI = confidence interval; TNF = tumor necrosis factor. a ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration (2.2)]. b Treatment difference (adjusted for stratification factors of prior anti-TNF exposure and corticosteroid use at baseline). c Clinical remission is defined as: rectal bleeding subscore = 0, stool frequency subscore = 0 or 1 (and a decrease from baseline in the stool frequency subscore of ≥ 1 point), and endoscopy subscore = 0 or 1 without friability. d Clinical response is defined as a reduction from baseline in the 3-component Mayo score of ≥ 2 points and ≥ 35%, and a reduction from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1. e Endoscopic improvement is defined as a Mayo endoscopy subscore of 0 or 1 without friability. f Endoscopic-histologic mucosal improvement is defined as both Mayo endoscopic 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, i.e., Geboes < 2.0). g p<0.0001. h p<0.001.
Endpoint	ZEPOSIA 0.92 mg Once Dailya (N=429)		Placebo (N=216)		Treatment Differenceb (95% CI)
Endpoint	n	%	n	%	Treatment Differenceb (95% CI)
Clinical remissionc	79	18%	13	6%	12% (8%, 17%)g
Without prior TNF blocker exposure	66/299	22%	10/151	7%
Prior TNF blocker exposure	13/130	10%	3/65	5%
Clinical responsed	205	48%	56	26%	22% (14%, 29%)g
Without prior TNF blocker exposure	157/299	53%	44/151	29%
Prior TNF blocker exposure	48/130	37%	12/65	19%
Endoscopic improvemente	117	27%	25	12%	16% (10%, 22%)g
Without prior TNF blocker exposure	97/299	32%	18/151	12%
Prior TNF blocker exposure	20/130	15%	7/65	11%
Endoscopic-histologic mucosal improvementf	54	13%	8	4%	9% (5%, 13%)h
Without prior TNF blocker exposure	47/299	16%	6/151	4%
Prior TNF blocker exposure	7/130	5%	2/65	3%

The relationship of endoscopic-histologic mucosal improvement, as defined in UC Study 1, at Week 10 to disease progression and long term outcomes was not evaluated during UC Study 1.

Rectal Bleeding Subscore and Stool Frequency Subscores

Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 (i.e., 1 week after completing the required 7-day dosage titration) in patients treated with ZEPOSIA.

UC Study 2

In UC Study 2, a total of 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.

Patients were permitted to be on stable doses of oral aminosalicylates. Corticosteroid tapering was required upon entering this study for patients who were receiving corticosteroids during the induction period. Concomitant oral immunomodulators or biologic therapies were not permitted. At study entry, 35% of patients were in clinical remission; 29% of patients were on corticosteroids; and 31% of patients had an inadequate response, loss of response, or intolerance to TNF blockers.

The primary endpoint was the proportion of patients in clinical remission at Week 52. The secondary endpoints at Week 52 were the proportion of patients with clinical response, endoscopic improvement, endoscopic-histologic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission at Week 52 among patients who achieved clinical remission at Week 10 in UC Study 1.

The results of the efficacy endpoints in the maintenance period are shown in Table 10.

Table 10: Proportion of Patients Meeting Efficacy Endpoints in the Maintenance Period at Week 52 in UC Study 2
CI = confidence interval; TNF = tumor necrosis factor. a ZEPOSIA was initiated with a 7-day titration [see Dosage and Administration (2.2)]. b Treatment difference (adjusted for stratification factors of clinical remission and concomitant corticosteroid use at Week 10). c Clinical remission is defined as: rectal bleeding subscore = 0, stool frequency subscore = 0 or 1 (and a decrease from baseline in the stool frequency subscore of ≥ 1 point), and endoscopy subscore = 0 or 1 without friability. d Clinical response is defined as a reduction from baseline in the 3-component Mayo score of ≥ 2 points and ≥ 35%, and a reduction from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of 0 or 1. e Endoscopic improvement is defined as a Mayo endoscopy subscore of 0 or 1 without friability. f Maintenance of remission is defined as clinical remission at Week 52 in the subset of patients in clinical remission at Week 10. g Corticosteroid-free remission is defined as clinical remission at Week 52 while off corticosteroids for ≥ 12 weeks. h Endoscopic-histologic mucosal improvement is defined as both Mayo endoscopic score 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, i.e., Geboes <2.0). i p<0.0001. j p<0.001. k p=0.0025.
Endpoint	ZEPOSIA 0.92 mg Once Dailya (N=230)		Placebo (N=227)		Treatment Differenceb (95% CI)
Endpoint	n	%	n	%	Treatment Differenceb (95% CI)
Clinical remissionc	85	37%	42	19%	19% (11%, 26%)i
Without prior TNF blocker exposure	63/154	41%	35/158	22%
Prior TNF blocker exposure	22/76	29%	7/69	10%
Clinical responsed	138	60%	93	41%	19% (10%, 28%)i
Without prior TNF blocker exposure	96/154	62%	76/158	48%
Prior TNF blocker exposure	42/76	55%	17/69	25%
Endoscopic improvemente	105	46%	60	26%	19% (11%, 28%)j
Without prior TNF blocker exposure	77/154	50%	48/158	30%
Prior TNF blocker exposure	28/76	37%	12/69	17%
Maintenance of clinical remission at Week 52 in the subset of patients in remission at Week 10f	41/79	52%	22/75	29%	24% (9%, 39%)k
Without prior TNF blocker exposure	37/64	58%	19/58	33%
Prior TNF blocker exposure	4/15	27%	3/17	18%
Corticosteroid-free clinical remissiong	73	32%	38	17%	15% (8%, 23%)j
Without prior TNF blocker exposure	55/154	36%	31/158	20%
Prior TNF blocker exposure	18/76	24%	7/69	10%
Endoscopic-histologic mucosal improvementh	68	30%	32	14%	16% (8%, 23%)j
Without prior TNF blocker exposure	51/154	33%	28/158	18%
Prior TNF blocker exposure	17/76	22%	4/69	6%

The relationship of endoscopic-histologic mucosal improvement, as defined in UC Study 2, at Week 52 to disease progression and long term outcomes was not evaluated during UC Study 2.