14 CLINICAL STUDIES

14.1 Psoriatic Arthritis

The safety and efficacy of OTEZLA was evaluated in 3 multicenter, randomized, double-blind, placebo-controlled trials (Studies PsA-1, PsA-2, and PsA-3) of similar design. A total of 1493 adult patients with active PsA (≥3 swollen joints and ≥3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug (DMARD) therapy were randomized. Patients enrolled in these studies had a diagnosis of PsA for at least 6 months. One qualifying psoriatic skin lesion of at least 2 cm in diameter was required in Study PsA- 3. Previous treatment with a biologic, including TNF-blockers was allowed (up to 10% could be TNF-blocker therapeutic failures). Across the 3 studies, patients were randomly assigned to placebo (n=496), OTEZLA 20 mg (n=500), or OTEZLA 30 mg (n=497) given orally twice daily. Titration was used over the first 5 days [see Dosage and Administration (2.1)]. Patients were allowed to receive stable doses of concomitant methotrexate [MTX (≤25 mg/week)], sulfasalazine [SSZ (≤2 g/day)], leflunomide [LEF (≤20 mg/day)], low dose oral corticosteroids (equivalent to ≤10 mg of prednisone a day), and/or nonsteroidal anti-inflammatory drugs (NSAIDs) during the trial. Treatment assignments were stratified based on small-molecule DMARD use at baseline in Studies PsA-1, PsA-2 and PsA-3. There was an additional stratification of BSA >3% with psoriasis in study PsA-3. The patients who were therapeutic failures of >3 agents for PsA (small molecules or biologics), or >1 biologic TNF blocker were excluded.

The primary endpoint was the percentage of patients achieving American College of Rheumatology (ACR) 20 response at Week 16. Placebo-controlled efficacy data were collected and analyzed through Week 24. Patients whose tender and swollen joint counts had not improved by at least 20% were considered non-responders at Week 16. Placebo non-responders were re-randomized 1:1 in a blinded fashion to either OTEZLA 20 mg twice daily or 30 mg twice daily following the titration schema [see Dosage and Administration (2.1)]. OTEZLA patients remained on their initial treatment. At Week 24, all remaining placebo patients were re-randomized to either 20 mg twice daily or 30 mg twice daily.

Patients with subtypes of PsA were enrolled across the 3 studies, including symmetric polyarthritis (62.0%), asymmetric oligoarthritis (27.0%), distal interphalangeal (DIP) joint arthritis (6.0%), arthritis mutilans (3.0%), and predominant spondylitis (2.1%). The median duration of PsA disease was 5 years. Patients received concomitant therapy with at least one DMARD (65.0%), MTX (55.0%), SSZ (9.0%), LEF (7.0%), low dose oral corticosteroids (14.0%), and NSAIDs (71.0%). Prior treatment with small-molecule DMARDs only was reported in 76.0% of patients and prior treatment with biologic DMARDs was reported in 22.0% of patients, which includes 9.0% who had failed prior biologic DMARD treatment.

Clinical Response in Patients with Psoriatic Arthritis

The percent of patients achieving ACR 20, 50 and 70 responses in Studies PsA-1, PsA-2, and PsA-3 are presented in Table 5 below. OTEZLA ± DMARDs, compared with Placebo ± DMARDs resulted in a greater improvement in signs and symptoms of psoriatic arthritis as demonstrated by the proportion of patients with an ACR 20 response at Week 16.

Table 5: Proportion of Patients With ACR Responses in Studies PsA-1, PsA-2 and PsA-3
a N is number of randomized and treated patients. b Statistically significantly different from placebo (p<0.05).
	PsA-1		PsA-2		PsA-3
Na	Placebo ± DMARDs N=168	OTEZLA 30 mg twice daily ± DMARDs N=168	Placebo ± DMARDs N=159	OTEZLA 30 mg twice daily ± DMARDs N=162	Placebo ± DMARDs N=169	OTEZLA 30 mg twice daily ± DMARDs N=167
ACR 20 Week 16	19%	38% b	19%	32% b	18%	41% b
ACR 50 Week 16	6%	16%	5%	11%	8%	15%
ACR 70 Week 16	1%	4%	1%	1%	2%	4%

OTEZLA 30 mg twice daily resulted in improvement for each ACR component, compared to placebo at Week 16 in Study PsA-1 (Table 6). Consistent results were observed in Studies PsA-2 and PsA-3.

Table 6: ACR Components Mean Change from Baseline at Week 16 in Study PsA- 1
Mean changes from baseline are least square means from analyses of covariance. a Scale 0-78. b Scale 0-76. c VAS=Visual Analog Scale; 0=best, 100=worst. d HAQ-DI=Health Assessment Questionnaire-Disability Index; 0=best, 3=worst; measures the subject's ability to perform the following: dress/groom, arise, eat, walk, reach, grip, maintain hygiene, and maintain daily activity. e CRP=C-reactive protein; Reference range 0-0.5 mg/dL. * N reflects randomized patients; actual number of patients evaluable for each endpoint may vary by timepoint.
	Placebo (N*=168)	OTEZLA 30 mg twice daily (N*=168)
Number of tender jointsa Sample Size Baseline Mean Change at Week 16	166 23 -2	164 23 -7
Number of swollen jointsb Sample Size Baseline Mean Change at Week 16	166 13 -2	164 13 -5
Patient's assessment of painc Sample Size Baseline Mean Change at Week 16	165 61 -6	159 58 -14
Patient's global assessment of disease activityc Sample Size Baseline Mean Change at Week 16	165 59 -3	159 56 -10
Physician's global assessment of disease activityc Sample Size Baseline Mean Change at Week 16	158 55 -8	159 56 -19
HAQ-DId score Sample Size Baseline Mean Change at Week 16	165 1.2 -0.09	159 1.2 -0.2
CRPe Sample Size Baseline Mean Change at Week 16	166 1.1 0.1	167 0.8 -0.1

Treatment with OTEZLA resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.

Physical Function Response

OTEZLA 30 mg twice daily demonstrated a greater improvement compared to placebo in mean change from baseline for the Health Assessment Questionnaire Disability Index (HAQ-DI) score at Week 16 [-0.244 vs. -0.086, respectively; 95% CI for the difference was (-0.26, -0.06)] in Study PsA-1. The proportions of HAQ-DI responders (≥0.3 improvement from baseline) at Week 16 for the OTEZLA 30 mg twice daily group were 38%, compared to 27%, for the placebo group in Study PsA-1. Consistent results were observed in Studies PsA-2 and PsA-3.

14.2 Psoriasis

Two multicenter, randomized, double-blind, placebo-controlled trials (Studies PSOR-1 and PSOR-2) enrolled a total of 1257 subjects 18 years of age and older with moderate to severe plaque psoriasis [body surface area (BSA) involvement of ≥10%, static Physician Global Assessment (sPGA) of ≥3 (moderate or severe disease), Psoriasis Area and Severity Index (PASI) score ≥12, candidates for phototherapy or systemic therapy]. Subjects were allowed to use low-potency topical corticosteroids on the face, axilla and groin. Subjects with scalp psoriasis were allowed to use coal tar shampoo and/or salicylic acid scalp preparations on scalp lesions.

Study PSOR-1 enrolled 844 subjects and Study PSOR-2 enrolled 413 subjects. In both studies, subjects were randomized 2:1 to OTEZLA 30 mg BID or placebo for 16 weeks. Both studies assessed the proportion of subjects who achieved PASI-75 at Week 16 and the proportion of subjects who achieved a sPGA score of clear (0) or almost clear (1) at Week 16. Across both studies, subjects ranged in age from 18 to 83 years, with an overall median age of 46 years. The mean baseline BSA involvement was 25.19% (median 21.0%), the mean baseline PASI score was 19.07 (median 16.80), and the proportion of subjects with sPGA score of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. Approximately 30% of all subjects had received prior phototherapy and 54% had received prior conventional systemic and/or biologic therapy for the treatment of psoriasis with 37% receiving prior conventional systemic therapy and 30% receiving prior biologic therapy. Approximately one-third of subjects had not received prior phototherapy, conventional systemic nor biologic therapy. A total of 18% of subjects had a history of psoriatic arthritis.

Clinical Response in Subjects with Plaque Psoriasis

The proportion of subjects who achieved PASI -75 responses, and sPGA score of clear (0) or almost clear (1), are presented in Table 7.

Table 7: Clinical Response at Week 16 in Studies PSOR-1 and PSOR-2
a N is number of randomized and treated patients. b PASI=Psoriasis Area and Severity Index. c sPGA=Static Physician Global Assessment.
	Study PSOR-1		Study PSOR-2
	Placebo	OTEZLA 30 mg BID	Placebo	OTEZLA 30 mg BID
Na	N=282	N=562	N=137	N=274
PASIb-75, n (%)	15 (5.3)	186 (33.1)	8 (5.8)	79 (28.8)
sPGAc of Clear or Almost Clear, n (%)	11 (3.9)	122 (21.7)	6 (4.4)	56 (20.4)

The median time to loss of PASI-75 response among the subjects re-randomized to placebo at Week 32 during the Randomized Treatment Withdrawal Phase was 5.1 weeks.

14.3 Oral Ulcers Associated with Behçet's Disease

A multicenter, randomized, placebo-controlled trial (BCT-002) enrolled a total of 207 adult patients with BD with active oral ulcers. Patients were previously treated with at least one nonbiologic BD medication and were candidates for systemic therapy. Patients met the International Study Group (ISG) Criteria for BD. Patients had at least 2 oral ulcers at screening and at least 2 oral ulcers at randomization and without currently active major organ involvement. Concomitant treatment for BD was not allowed.

Patients were randomized 1:1 to receive either OTEZLA 30 mg twice daily (n=104) or placebo (n=103) for 12 weeks. After Week 12, all patients received OTEZLA 30 mg twice daily.

Efficacy was assessed based on the number and pain of oral ulcers.

Patients ranged in age from 19 to 72, with a mean age of 40 years. The mean duration of BD was 6.84 years. All subjects had a history of recurrent oral ulcers that were currently active. Subjects had a history of skin lesions (98.6%), genital ulcers (90.3%), musculoskeletal manifestations (72.5%), ocular manifestations (17.4%), central nervous system (9.7%), gastrointestinal (GI) manifestations (9.2%) and vascular involvement (1.4%). The mean baseline oral ulcer counts were 4.2 and 3.9 in the OTEZLA and placebo groups, respectively.

Measures of Oral Ulcers

Improvements in measures of oral ulcers at Week 12 are presented in Table 8.

Table 8: Clinical Response of Oral Ulcers at Week 12 in the BCT-002 Study (ITT* Population)
Endpoint	Placebo N=103	OTEZLA 30 mg twice daily N=104	Treatment Difference† (95% CI‡)
* ITT=intent to treat. † OTEZLA – Placebo. ‡ CI=confidence interval. § Mean changes from baseline are least square means from mixed-effects model for repeated measures, adjusting for sex, region, and baseline pain of oral ulcers as measured by the visual analog scale. ¶ VAS=visual analog scale; 0=no pain, 100=worst possible pain. # Patients for whom data are not available to determine response status are considered non-responders. Þ Adjusted difference in proportions is the weighted average of the treatment differences across the 4 strata of combined sex and region factors with the Cochran-Mantel-Haenszel weights. ß Mean daily averages are least squares means from analysis of covariance, after adjusting for sex, region, and baseline number of oral ulcers. à Based on oral ulcer counts measured at baseline and at Weeks 1, 2, 4, 6, 8, 10, and 12.
Change§ from baseline in the pain of oral ulcers as measured by VAS¶ at Week 12	-18.7	- 42.7	-24.1 (-32.4, -15.7)
Proportion# of subjects achieving oral ulcer complete response (oral ulcer-free) at Week 12	22.3%	52.9%	30.6%Þ (18.1%, 43.1%)
Proportion# of subjects achieving oral ulcer complete response (oral ulcer-free) by Week 6, and who remained oral ulcer-free for at least 6 additional weeks during the 12-week Placebo-controlled Treatment Phase	4.9%	29.8%	25.1%Þ (15.5%, 34.6%)
Daily averageß,à number of oral ulcers during the 12-week Placebo-controlled Treatment Phase	2.6	1.5	-1.1 (-1.6, -0.7)

Figure 1 displays the mean number of oral ulcers for each treatment group at each visit, while Figure 2 displays the mean oral ulcer pain on a visual analog scale for each treatment group at each visit.

ITT = intent-to-treat; SE = standard error.

Figure 1: Mean (± SE) Number of Oral Ulcers by Time Point Through Week 12 (ITT Population)

ITT=intent-to-treat; SE=standard error.
Oral ulcer pain was assessed on a 100-mm Visual Analog Scale with 0 = no pain and 100 = worst possible pain. Mean baseline Visual Analog Scale pain scores were 61.2 and 60.8 in the OTEZLA 30 mg twice daily treatment group and placebo treatment group, respectively.

Figure 2: Mean (± SE) Oral Ulcer Pain on a Visual Analog Scale by Time Point Through Week 12 (ITT Population)