14 CLINICAL STUDIES

14.1 Adult Plaque Psoriasis

Four multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous COSENTYX (Trials PsO1, PsO2, PsO3, and PsO4) enrolled 2,403 subjects (691 randomized to COSENTYX 300 mg, 692 to COSENTYX 150 mg, 694 to placebo, and 323 to a biologic active control) 18 years of age and older with PsO who had a minimum BSA involvement of 10%, and Psoriasis Area and Severity Index (PASI) score greater than or equal to 12, and who were candidates for phototherapy or systemic therapy. In these studies, each 300 mg dose was administered as two injections of 150 mg.

Trial PsO1 (NCT01365455) enrolled 738 subjects (245 randomized to COSENTYX 300 mg, 245 to COSENTYX 150 mg, and 248 to placebo). Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. Subjects randomized to receive placebo that were non-responders at Week 12 were crossed over to receive COSENTYX (either 300 mg or 150 mg) at Weeks 12, 13, 14, 15, and 16 followed by the same dose every 4 weeks. All subjects were followed for up to 52 weeks following first administration of trial treatment.
Trial PsO2 (NCT01358578) enrolled 1306 subjects (327 randomized to COSENTYX 300 mg, 327 to COSENTYX 150 mg, 326 to placebo, and 323 to a biologic active control). Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. Subjects randomized to receive placebo that were non-responders at Week 12 crossed over to receive COSENTYX (either 300 mg or 150 mg) at Weeks 12, 13, 14, 15, and 16 followed by the same dose every 4 weeks. All subjects were followed for up to 52 weeks following first administration of trial treatment.
Trial PsO3 (NCT01555125) enrolled 177 subjects (59 randomized to COSENTYX 300 mg, 59 to COSENTYX 150 mg, and 59 to placebo) and assessed safety, tolerability, and usability of COSENTYX self-administration via prefilled syringe for 12 weeks. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks total.
Trial PsO4 (NCT01636687) enrolled 182 subjects (60 randomized to COSENTYX 300 mg, 61 to COSENTYX 150 mg, and 61 to placebo) and assessed safety, tolerability, and usability of COSENTYX self-administration via Sensoready pen for 12 weeks. Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks total.

Endpoints

In all trials, the endpoints were the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline to Week 12 and treatment success (clear or almost clear) on the Investigator’s Global Assessment modified 2011 (IGA). Other evaluated outcomes included the proportion of subjects who achieved a reduction in PASI score of at least 90% (PASI 90) from baseline at Week 12, maintenance of efficacy to Week 52, and improvements in itching, pain, and scaling at Week 12 based on the Psoriasis Symptom Diary©.

The PASI is a composite score that takes into consideration both the percentage of BSA affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema, and scaling). The IGA is a 5-category scale, including “0 = clear”, “1 = almost clear”, “2 = mild”, “3 = moderate” or “4 = severe” indicating the physician’s overall assessment of the psoriasis severity focusing on induration, erythema, and scaling. Treatment success of “clear” or “almost clear” consisted of no signs of psoriasis or normal to pink coloration of lesions, no thickening of the plaque, and none to minimal focal scaling.

Baseline Disease Characteristics

Across all treatment groups, the baseline PASI score ranged from 11 to 72 with a median of 20 and the baseline IGA score ranged from “moderate” (62%) to “severe” (38%). Of the 2,077 PsO subjects who were included in the placebo-controlled trials, 79% were biologic-naïve (have never received a prior treatment with biologics) and 45% were non-biologic failures (failed to respond to a prior treatment with non-biologic therapies). Of the subjects who received a prior treatment with biologics, over one-third were biologic failures. Approximately 15% to 25% of trial subjects had a history of psoriatic arthritis.

Clinical Response

The results of Trials PsO1 and PsO2 are presented in Table 3.

Table 3: Clinical Outcomes at Week 12 in Adults With PsO in Trials PsO1 and PsO2 (Subcutaneous Treatment)
	Trial PsO1			Trial PsO2
	COSENTYX 300 mg (N = 245) n (%)	COSENTYX 150 mg (N = 245) n (%)	Placebo (N = 248) n (%)	COSENTYX 300 mg (N = 327) n (%)	COSENTYX 150 mg (N = 327) n (%)	Placebo (N = 326) n (%)
PASI 75 response	200 (82)	174 (71)	11 (4)	249 (76)	219 (67)	16 (5)
IGA of clear or almost clear	160 (65)	125 (51)	6 (2)	202 (62)	167 (51)	9 (3)

The results of Trials PsO3 and PsO4 are presented in Table 4.

Table 4: Clinical Outcomes at Week 12 in Adults With PsO in Trials PsO3 and PsO4 (Subcutaneous Treatment)
	Trial PsO3			Trial PsO4
	COSENTYX 300 mg (N = 59) n (%)	COSENTYX 150 mg (N = 59) n (%)	Placebo (N = 59) n (%)	COSENTYX 300 mg (N = 60) n (%)	COSENTYX 150 mg (N = 61) n (%)	Placebo (N = 61) n (%)
PASI 75 response	44 (75)	41 (69)	0 (0)	52 (87)	43 (70)	2 (3)
IGA of clear or almost clear	40 (68)	31 (53)	0 (0)	44 (73)	32 (52)	0 (0)

Examination of age, sex, and racial subgroups did not identify differences in response to COSENTYX among these subgroups. Based on post-hoc subgroup analyses in subjects with moderate to severe PsO, subjects with lower body weight and lower disease severity may achieve an acceptable response with COSENTYX 150 mg.

PASI 90 response at Week 12 was achieved with COSENTYX 300 mg and 150 mg compared to placebo in 59% (145/245) and 39% (95/245) versus 1% (3/248) of subjects, respectively (Trial PsO1) and 54% (175/327) and 42% (137/327) versus 2% (5/326) of subjects, respectively (Trial PsO2). Similar results were seen in Trials PsO3 and PsO4.

With continued treatment over 52 weeks, subjects in Trial PsO1 who were PASI 75 responders at Week 12 maintained their responses in 81% (161/200) of the subjects treated with COSENTYX 300 mg and in 72% (126/174) of subjects treated with COSENTYX 150 mg. Trial PsO1 subjects who were clear or almost clear on the IGA at Week 12 also maintained their responses in 74% (119/160) of subjects treated with COSENTYX 300 mg and in 59% (74/125) of subjects treated with COSENTYX 150 mg.
Similarly in Trial PsO2, PASI 75 responders maintained their responses in 84% (210/249) of subjects treated with COSENTYX 300 mg and in 82% (180/219) of subjects treated with COSENTYX 150 mg. Trial PsO2 subjects who were clear or almost clear on the IGA also maintained their responses in 80% (161/202) of subjects treated with COSENTYX 300 mg and in 68% (113/167) of subjects treated with COSENTYX 150 mg.

Among the subjects who chose to participate (39%) in assessments of patient reported outcomes, improvements in signs and symptoms related to itching, pain, and scaling at Week 12 compared to placebo (Trials PsO1 and PsO2) were observed using the Psoriasis Symptom Diary©.

Psoriasis Lesions of Scalp

A randomized, placebo-controlled trial (Trial PsO5; NCT02267135) enrolled 102 subjects with moderate to severe psoriasis lesions of scalp, defined as having a Psoriasis Scalp Severity Index (PSSI) score of greater than or equal to 12, an IGA scalp only score of 3 or greater, and at least 30% of the scalp affected. In this trial, 62% of subjects had at least 50% of scalp surface area affected. In this study, each 300 mg dose was administered as two injections of 150 mg. The proportions of subjects achieving an IGA scalp only score of 0 or 1 (clear or almost clear) were 56.9% and 5.9% for the COSENTYX 300 mg and the placebo groups, respectively.

300 mg/2 mL Pre-filled Syringe and 300 mg/2 mL UnoReady Pen

Two randomized, double-blind, placebo-controlled, 52-week trials (PsO6 and PsO7) enrolled 336 subjects at least 18 years of age with moderate to severe PsO who are candidates for systemic therapy or phototherapy to evaluate the safety and efficacy of COSENTYX 300 mg subcutaneously administered with a single 300 mg/2 mL prefilled syringe (Trial PsO6, NCT02748863, 214 patients) or with a single 300 mg/2 mL UnoReady pen (Trial PsO7, NCT03589885, 122 patients) compared to two subcutaneous injections using a 150 mg/1 mL prefilled syringe. The co-primary endpoints for both trials were the proportion of subjects who achieved a PASI 75 response and IGA mod 2011 ‘clear’ or ‘almost clear’ response with at least a two-grade reduction from baseline at Week 12.

Table 5: Clinical Outcomes at Week 12 in Adults With PsO in Trials PsO6 and PsO7 (Subcutaneous Treatment)
Abbreviation: PFS, prefilled syringe. Missing data was imputed using multiple imputation.
	Trial PsO6			Trial PsO7
	COSENTYX 300 mg			COSENTYX 300 mg
	2 mL PFS (N = 72) %	Two 1 mL PFS (N = 71) %	Placebo (N = 71) %	2 mL Pen (N = 41) %	Two 1 mL PFS (N = 41) %	Placebo (N = 40) %
IGA of clear or almost clear	76	69	1	76	68	8
PASI 75 response	89	82	2	95	83	10
PASI 90 response	67	70	2	76	62	5

14.2 Pediatric Plaque Psoriasis

A 52-week, multicenter randomized, double-blind, placebo and active-controlled trial (Trial PsO8; NCT02471144) enrolled 162 pediatric subjects 6 years of age and older, with severe plaque psoriasis (as defined by a PASI score ≥ 20, an IGA modified 2011 score of 4, and involving ≥ 10% of the BSA) who were candidates for systemic therapy.

Subjects were randomized to receive subcutaneous placebo, COSENTYX, or a biologic active control. In the COSENTYX groups, subjects with BW less than 25 kg received 75 mg, subjects with BW 25 to less than 50 kg received either 75 mg or 150 mg (2 times the recommended dose), and subjects with BW at least 50 kg received either 150 mg or 300 mg (2 times the recommended dose). In this study, each 300 mg dose was administered as two subcutaneous injections of 150 mg. Subjects in the COSENTYX and placebo groups received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4 followed by dosing every 4 weeks. At Week 12, subjects randomized to placebo who were non-responders were switched to COSENTYX (dose based on body weight) and received COSENTYX at Weeks 12, 13, 14, and 15, followed by the same dose every 4 weeks starting at Week 16.

Baseline Characteristics

Overall, 60% of the subjects were female, 83% were White, the median BW was 50.6 kg, and the mean age was 13.5 years with 23% of the subjects less than 12 years. At baseline, the median PASI score was 26 (ranged from 17 to 60), and 99% of the subjects had an IGA modified 2011 score of 4 (‘severe’). Approximately 43% of the subjects had prior exposure to phototherapy, 53% to conventional systemic therapy, 3% to biologics, and 9% had concomitant psoriatic arthritis.

Endpoints

The co-primary endpoints were the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline to Week 12 and the proportion of subjects who achieved an IGA modified 2011 score of ‘clear’ or ‘almost clear’ (0 or 1) with at least a 2-point improvement from baseline to Week 12. The key secondary endpoint was the proportion of subjects who achieved a reduction in PASI score of at least 90% (PASI 90) from baseline to Week 12.

Clinical Response

Table 6 presents the efficacy results at Week 12 by baseline weight strata for the approved dosage in Trial PsO8.

Table 6: Clinical Outcomes at Week 12 in Pediatric Subjects With Severe PsO in Trial PsO8 (Subcutaneous Treatment)
Non-responder imputation was used to handle missing values. aCOSENTYX treated subjects received 75 mg for subjects less than 50 kg and 150 mg for subjects at least 50 kg body weight.
	Body weight < 50 kg		Body weight ≥ 50 kg		Total
	COSENTYX 75 mg (N = 22) n (%)	Placebo (N = 20) n (%)	COSENTYX 150 mg (N = 21) n (%)	Placebo (N = 21) n (%)	COSENTYXa (N = 43) n (%)	Placebo (N = 41) n (%)
IGA of clear or almost clear	7 (32)	1 (5)	17 (81)	1 (5)	24 (56)	2 (5)
PASI 75 response	12 (55)	2 (10)	18 (86)	4 (19)	30 (70)	6 (15)
PASI 90 response	9 (41)	1 (5)	17 (81)	0 (0)	26 (60)	1 (2)

14.3 Adult Psoriatic Arthritis

The safety and efficacy of COSENTYX were assessed in 1,999 patients, in 3 randomized, double-blind, placebo-controlled trials (PsA1, PsA2, and PsA3) in adult patients, age 18 years and older with active PsA (greater than or equal to 3 swollen and greater than or equal to 3 tender joints) despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy. Patients in these trials had a diagnosis of PsA of at least 5 years across all trials.

PsA1 Study (NCT 01752634) evaluated 397 patients, who were treated with 75 mg, 150 mg or 300 mg of COSENTYX (administered as two subcutaneous injections of 150 mg) at Weeks 0, 1, 2, 3, and 4, followed by the same subcutaneous dose every 4 weeks. Patients who received placebo were re-randomized to receive subcutaneous COSENTYX (either 150 mg or 300 mg every 4 weeks) at Week 16 or Week 24 based on responder status. The primary endpoint was the percentage of patients achieving an ACR20 response at Week 24.
PsA2 Study (NCT 01392326) evaluated 606 patients, who were treated with intravenous secukinumab 10 mg/kg, or placebo at Weeks 0, 2, and 4, followed by either 75 mg or 150 mg of subcutaneous COSENTYX treatment (or placebo) every 4 weeks. Patients who received placebo were re-randomized to receive subcutaneous COSENTYX (either 75 mg or 150 mg every 4 weeks) at Week 16 or Week 24 based on responder status.
PsA3 Study (NCT 02404350) evaluated 996 patients, who were treated with 150 mg or 300 mg of COSENTYX (administered as two subcutaneous injections of 150 mg) at Weeks 0, 1, 2, 3, and 4 followed by the same subcutaneous dose every 4 weeks, or once every 4 weeks of COSENTYX 150 mg. Patients treated with placebo received subcutaneous COSENTYX, either 150 mg or 300 mg, per baseline randomization, at Week 16 or Week 24 based upon responder status. The primary endpoint was ACR20 response at Week 16 with the key secondary endpoint the change from baseline in modified Total Sharp Score (mTSS) at Week 24.

Baseline Disease Characteristics

At baseline, over 61% and 42% of the patients had enthesitis and dactylitis, respectively. Overall, 31% of patients discontinued previous treatment with anti-TNFα agents due to either lack of efficacy or intolerance. In addition, approximately 53% of patients from both studies had concomitant methotrexate (MTX) use. Patients with different subtypes of PsA were enrolled, including polyarticular arthritis with no evidence of rheumatoid nodules (80%), asymmetric peripheral arthritis (63%), distal interphalangeal involvement (58%), spondylitis with peripheral arthritis (20%), and arthritis mutilans (7%).

Clinical Response

In PsA1, patients treated with 150 mg or 300 mg COSENTYX demonstrated a greater clinical response, including ACR20, ACR50, and ACR70 compared to patients treated with placebo at Week 24 (Table 7). Responses were similar in patients regardless of concomitant MTX treatment. Responses were seen regardless of prior anti-TNFα exposure.

In patients with coexistent PsO receiving COSENTYX (n = 99), the skin lesions of psoriasis improved with treatment, relative to placebo, as measured by the Psoriasis Area Severity Index (PASI).

Table 7: Responsesa in PsA1 Study at Week 16 and Week 24 (Subcutaneous Treatment)
aPatients who met escape criteria (less than 20% improvement in tender or swollen joint counts) at Week 16 were considered non-responders.
	COSENTYX	COSENTYX	Placebo	Difference from placebo (95% CI)
	150 mg (N = 100)	300 mg (N = 100)	(N = 98)	COSENTYX 150 mg	COSENTYX 300 mg
ACR20 response
Week 16 (%)	60	57	18	42 (30, 54)	38 (26, 51)
Week 24 (%)	51	54	15	36 (24, 48)	39 (27, 51)
ACR50 response
Week 16 (%)	37	35	6	31 (21, 42)	28 (18, 39)
Week 24 (%)	35	35	7	28 (18, 38)	28 (17, 38)
ACR70 response
Week 16 (%)	17	15	2	15 (7, 23)	13 (5, 20)
Week 24 (%)	21	20	1	20 (12, 28)	19 (11, 27)

The percentage of patients who achieved a ACR20 response by visit is shown in Figure 1. Patients on placebo who received COSENTYX without a loading regimen achieved similar ACR20 responses over time (data not shown).

Figure 1: Percent of Adult Patients Who Achieved ACR 20 Responsea in PsA1 Study Through Week 24 (Subcutaneous Treatment)

Figure 1: Percent of Patients Achieving ACR 20 Responsea in PsA1 Study Through Week 24 (Subcutaneous Treatment)

aPatients who met escape criteria (less than 20% improvement in tender or swollen joint counts) at Week 16 were considered non-responders.

The improvements in the components of the ACR response criteria in the PsA1 study are shown in Table 8.

Table 8: Mean Change From Baseline in ACR Components at Week 16a (PsA1 Study) (Subcutaneous Treatment)
aWeek 16 rather than Week 24 data are displayed to provide comparison between arms prior to placebo escape to COSENTYX. bMean change based upon observed data.
	COSENTYX 150 mg (N = 100)	COSENTYX 300 mg (N = 100)	Placebo (N = 98)
Number of swollen joints
Baseline	12.0	11.2	12.1
Mean change at Week 16	-4.86	-5.83	-3.22
Number of tender joints
Baseline	24.1	20.2	23.5
Mean change at Week 16	-10.70	-10.01	-1.77
Patient’s assessment of pain
Baseline	58.9	57.7	55.4
Mean change at Week 16	-22.91	-23.97	-7.98
Patient global assessment
Baseline	62.0	60.7	57.6
Mean change at Week 16	-25.47	-25.40	-8.25
Physician global assessment
Baseline	56.7	55.0	55.0
Mean change at Week 16	-29.24	-34.71	-14.95
Disability index (HAQ)
Baseline	1.2200	1.2828	1.1684
Mean change at Week 16	-0.45	-0.55	-0.23
CRP (mg/L)
Baseline	14.15	10.88	7.87
Mean change at Week 16b	-8.41	-7.21	0.79

Improvements in enthesitis and dactylitis scores were observed in each COSENTYX group compared to placebo at Week 24.

Radiographic Response

In PsA3 Study, inhibition of progression of structural damage was assessed radiographically and expressed by the modified mTSS and its components, the Erosion Score (ES) and Joint Space Narrowing Score (JSN), at Week 24 compared to baseline. Radiographs of hands, wrists, and feet were obtained at baseline, Week 16 and/or Week 24 and scored independently by at least two readers who were blinded to treatment group and visit number. Treatment with subcutaneous COSENTYX 150 mg without a loading dose, 150 mg with a loading dose and 300 mg with a loading dose significantly inhibited progression of peripheral joint damage compared with treatment with placebo as measured by change from baseline in mTSS at Week 24. The percentage of patients with no disease progression (defined as a change from baseline in mTSS of less than or equal to 0.0) from randomization to Week 24 was 75.7%, 70.9%, and 76.5% for COSENTYX 150 mg without a loading dose, 150 mg, 300 mg, respectively versus 68.2% for placebo.

Table 9: Rate of Change per 24 Weeks in Modified Total Sharp Score (Subcutaneous Treatment)
Results from a linear mixed effects model that excluded data after escape for placebo subjects who received escape therapy at Week 16. The model assumes approximately linear progression over time and estimates a difference in rates (slopes) of progression over 24 weeks to compare treatment arms.
Treatment	N	Rate of change per 24 weeks	Difference from placebo (95% CI)
COSENTYX 150 mg without a loading dose	210	-0.10	-0.61 (-0.95, -0.26)
COSENTYX 150 mg with a loading dose	213	0.14	-0.37 (-0.71, -0.03)
COSENTYX 300 mg with a loading dose	217	0.03	-0.48 (-0.82, -0.14)
Placebo	296	0.51	--

Physical Function

Improvement in physical function as assessed by Health Assessment Questionnaire-Disability Index (HAQ-DI) demonstrated that the proportion of patients who achieved at least -0.3 improvement in HAQ-DI score from baseline was greater in the subcutaneous COSENTYX 150 mg and 300 mg groups compared to the placebo group at Weeks 16 and 24. At Week 16 in PsA1 study, estimated mean change from baseline was -0.23 in the placebo group compared with -0.45 in the COSENTYX 150 mg group and -0.55 in the COSENTYX 300 mg group.

Treatment of Adult Patients with Active Psoriatic Arthritis with Intravenous COSENTYX

The effectiveness of intravenous COSENTYX in the treatment of adult patients with active PsA was extrapolated from the established effectiveness of subcutaneous COSENTYX in adult patients with active PsA based on pharmacokinetic exposure [see Clinical Pharmacology (12.3)].

14.4 Ankylosing Spondylitis

The safety and efficacy of subcutaneous COSENTYX were assessed in 816 adult patients (18 years of age and older) with active AS in three randomized, double-blind, placebo-controlled trials (AS1, AS2, and AS3). Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) greater or equal to 4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy.

AS1 Study (NCT01649375) evaluated 219 patients, who were treated with 75 mg or 150 mg of subcutaneous COSENTYX treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks. At Week 16, patients who received placebo were re-randomized to either 75 mg or 150 mg of subcutaneous COSENTYX every 4 weeks. The primary endpoint was the percentage of patients who achieved an ASAS20 response at Week 16.
AS2 Study (NCT01358175) evaluated 371 patients, who were treated with intravenous secukinumab 10 mg/kg at Weeks 0, 2, and 4 (for both treatment arms) or placebo, followed by either 75 mg or 150 mg subcutaneous COSENTYX treatment every 4 weeks or placebo. Patients who received placebo were re-randomized to receive subcutaneous COSENTYX (either 75 mg or 150 mg every 4 weeks) at Week 16 or Week 24 based on responder status.
AS3 Study (NCT02008916) evaluated 226 patients, who were treated with intravenous secukinumab 10 mg/kg at Weeks 0, 2, and 4 (for both treatment arms) or placebo, followed by either 150 mg or 300 mg subcutaneous COSENTYX treatment every 4 weeks or placebo. Patients who received placebo were re-randomized to receive subcutaneous COSENTYX (either 150 mg or 300 mg every 4 weeks) at Week 16. The primary endpoint was the percentage of patients who achieved an ASAS20 response at Week 16. Patients were blinded to the treatment regimen up to Week 52, and the trial continued to Week 156. In this study, each 300 mg dose was administered as two injections of 150 mg.

Baseline Disease Characteristics

At baseline, approximately 13% and 25% used concomitant MTX or sulfasalazine, respectively. Overall, 29% of patients discontinued previous treatment with anti-TNFα agents due to either lack of efficacy or intolerance.

Clinical Response

In AS1, patients treated with 150 mg COSENTYX demonstrated greater improvements in ASAS20 and ASAS40 responses compared to patients treated with placebo at Week 16 (Table 10). Responses were similar in patients regardless of concomitant therapies.

Table 10: ASAS20 and ASAS40 Responses in All AS Patients at Week 16 in Study AS1 (Subcutaneous Treatment)
	COSENTYX 150 mg (n = 72)	Placebo (n = 74)	Difference from placebo (95% CI)
ASAS20 response, %	61	28	33 (18, 48)
ASAS40 response, %	36	11	25 (12, 38)

The improvements in the main components of the ASAS20 response criteria and other measures of disease activity are shown in Table 11.

Table 11: ASAS20 Components and Other Measures of Disease Activity at Week 16 (AS1 Study) (Subcutaneous Treatment)
Percent of subjects with at least a 20%- and 10-unit improvement measured on a Visual Analog Scale (VAS) with 0 = none, 100 = severe. Bath Ankylosing Spondylitis Functional Index. Inflammation is the mean of two patient-reported stiffness self-assessments in BASDAI. Bath Ankylosing Spondylitis Disease Activity Index. Bath Ankylosing Spondylitis Metrology Index. High sensitivity C-reactive protein / mean change based upon observed data.
	COSENTYX 150 mg (N = 72)		Placebo (N = 74)
	Baseline	Week 16 change from baseline	Baseline	Week 16 change from baseline
ASAS20 response criteria
-Patient Global Assessment of Disease Activity (0-100 mm)1	67.5	-27.7	70.5	-12.9
-Total spinal pain (0-100 mm)	66.2	-28.5	69.2	-10.9
-BASFI (0-10)2	6.2	-2.2	6.1	-0.7
-Inflammation (0-10)3	6.5	-2.5	6.5	-0.8
BASDAI score4	6.6	-2.2	6.8	-0.9
BASMI5	3.6	-0.51	3.9	-0.22
hsCRP6 (mg/L) mean change at Week 16	27.0	-17.2	15.9	0.8

The percentage of patients who achieved ASAS20 responses by visit is shown in Figure 2. Patients on placebo who received COSENTYX without a loading regimen achieved similar ASAS20 responses over time (data not shown).

Figure 2: ASAS20 Responses in All AS1 Study Patients Over Time Up to Week 16 (Subcutaneous Treatment)

Figure 2: ASAS20 Responses in All AS1 Study Patients Over Time Up to Week 16 (Subcutaneous Treatment)

In AS3 Study, patients treated with subcutaneous COSENTYX (150 mg and 300 mg) demonstrated improved signs and symptoms, and had comparable efficacy responses, regardless of dose, that were superior to placebo at Week 16 for the primary and most secondary endpoints. At Week 16, the ASAS20 and ASAS40 responses were 58.1% and 40.5% for 150 mg and 60.5% and 42.1% for 300 mg, respectively. The percent of patients achieving ASAS20 responses by visit is shown in Figure 3.

COSENTYX treated patients showed improvement compared to placebo-treated patients in health-related quality of life as assessed by ASQoL at Week 16.

Figure 3: ASAS20 Responses in All AS3 Study Patients Over Time Up to Week 16 (Subcutaneous Treatment)

Figure 3: ASAS20 Responses in All AS3 Study Patients Over Time Up to Week 16 (Subcutaneous Treatment)

Treatment of Adult Patients with Active Ankylosing Spondylitis with Intravenous COSENTYX

The effectiveness of intravenous COSENTYX in the treatment of adult patients with active AS was extrapolated from the established effectiveness of subcutaneous COSENTYX in adult patients with active AS based on pharmacokinetic exposure [see Clinical Pharmacology (12.3)].

14.5 Non-Radiographic Axial Spondyloarthritis

The safety and efficacy of COSENTYX were assessed in 555 adult patients (18 years of age and older) with active nr-axSpA in one randomized, double-blind, placebo-controlled Phase 3 study (nr-axSpA1, NCT02696031). Patients met ASAS criteria for axSpA with objective signs of inflammation and had active disease as defined by a BASDAI greater or equal to 4, a Visual Analogue Scale (VAS) for total back pain greater or equal to 40 (on a scale of 0-100 mm) despite NSAID therapy and no evidence of radiographic changes in the sacroiliac joints that would meet the modified New York criteria for AS. Patients also had to have objective signs of inflammation with a C-reactive protein (CRP) level above the upper limit of normal and/or evidence of sacroiliitis on Magnetic Resonance Imaging (MRI).

Patients were treated with 150 mg of subcutaneous COSENTYX treatment with a loading dosage (Weeks 0, 1, 2, 3, and 4) or without a loading dosage (Weeks 0 and 4) followed by the same dose every 4 weeks or placebo. In the double-blind period, patients (n = 555) received either placebo or COSENTYX for 52 weeks. Starting Week 16, dosage adjustment or addition of concomitant NSAIDs and DMARDs was permitted. Starting at Week 20, patients were allowed to switch to open-label 150 mg of subcutaneous COSENTYX monthly or other biologic at the discretion of the investigator and patient. The primary endpoint was at least 40% improvement in Assessment of Spondyloarthritis International Society (ASAS40) at Week 52.

Baseline Disease Characteristics

Approximately 10% and 15% of patients used concomitant MTX or sulfasalazine, respectively. Overall, 10% of patients had received previous treatment with anti-TNFα agents and discontinued these due to either lack of efficacy or intolerance.

Clinical Response

In nr-axSpA1 Study, treatment with COSENTYX 150 mg resulted in significant improvements in the measure of disease activity compared to treatment with placebo at Week 16 and Week 52 (Table 12).

Table 12: Clinical Response in the nr-axSpA1 Study at Week 16 and Week 52 (Subcutaneous Treatment)
Difference in proportions with 95% CI based on normal approximation.
Number of subjects with ASAS40 response (%)	COSENTYX 150 mg without load (n = 184)	COSENTYX 150 mg with load (n = 185)		Difference from placebo (95% CI)
			Placebo (n = 186)	COSENTYX 150 mg without load	COSENTYX 150 mg with load
Week 16	75 (41)	74 (40)	52 (28)	13 (3, 22)	12 (2, 22)
Week 52	70 (38)	62 (34)	36 (19)	19 (10, 28)	14 (5, 23)

The results of the main components of the ASAS40 response criteria in the nr-axSpA1 Study are shown in Table 13.

Table 13: Main Components of the ASAS40 Response Criteria and Other Measures of Disease Activity in nr-axSpA Patients at Baseline and Week 16 in the nr-axSpA1 Study (Subcutaneous Treatment)
	COSENTYX 150 mg without loading dosage (N = 184)		COSENTYX 150 mg with a loading dosage (N = 185)		Placebo (N = 186)
	Baseline	Week 16 change from baseline	Baseline	Week 16 change from baseline	Baseline	Week 16 change from baseline
ASAS40 response criteria
-Patient Global Assessment of Disease Activity (0-100 mm)	71.0	-26.2	72.6	-24.1	68.8	-13.8
-Total back pain (0-100 mm)	72.0	-25.5	73.3	-25.0	70.9	-15.6
-BASFI (0-10)	5.9	-1.6	6.2	-1.8	5.9	-1.0
-Inflammation (0-10)	6.8	-2.8	7.2	-2.8	6.6	-1.7
hsCRP (mg/L) mean change at Week 16	9.8	-4.7	13.4	-7.9	9.2	-2.4
BASDAI (0-10)	6.9	-2.4	7.1	-2.4	6.8	-1.5
-Spinal pain	7.6	-3.0	7.8	-3.0	7.5	-2.0
-Peripheral pain and swelling (0-10)	6.6	-2.4	6.3	-2.3	6.1	-1.6
BASMI	2.8	-0.3	2.9	-0.3	2.8	-0.1

The percentage of patients achieving an ASAS40 response by visit is shown in Figure 4.

Figure 4: ASAS40 Responses in nr-axSpA1 Study Over Time up to Week 16 (Subcutaneous Treatment)

Figure 4: ASAS40 Responses in nr-axSpA1 Study Over Time up to Week 16 (Subcutaneous Treatment)

Health-Related Quality of Life

COSENTYX treated patients showed improvement in both loading and without loading dosage arms compared to placebo-treated patients at Week 16 in health-related quality of life as measured by ASQoL (LS mean change: Week 16: -3.5 and -3.6 versus -1.8, respectively).

Treatment of Adult Patients with Active Non-radiographic Axial Spondyloarthritis with Intravenous COSENTYX

The effectiveness of intravenous COSENTYX in the treatment of adult patients with active nr-axSpA was extrapolated from the established effectiveness of subcutaneous COSENTYX in adult patients with active nr-axSpA based on pharmacokinetic exposure [see Clinical Pharmacology (12.3)].

14.6 Juvenile Psoriatic Arthritis and Enthesitis-Related Arthritis

The efficacy and safety of subcutaneous secukinumab were assessed in a two-year, 3-part, double-blind, placebo-controlled, event-driven, randomized, Phase 3 study (NCT03031782) in 86 pediatric patients (2 to less than 18 years of age) with active ERA or JPsA as diagnosed based on a modified International League of Associations for Rheumatology (ILAR) Juvenile Idiopathic Arthritis (JIA) classification criteria. The trial consisted of an open-label portion (Part 1) followed by randomized withdrawal (Part 2) followed by open-label treatment (Part 3). Patients were given subcutaneous doses of 75 mg if they weighed less than 50 kg, or subcutaneous doses of 150 mg if they weighed at least 50 kg or greater, administered by subcutaneous injection at Weeks 0, 1, 2, 3, and 4, and every 4 weeks thereafter.

The primary endpoint was time to flare in Part 2. Disease flare was defined as at least 30% worsening in at least three of the six JIA ACR response criteria and at least 30% improvement in not more than one of the six JIA ACR response criteria and a minimum of two active joints.

In open-label Part 1, all patients received subcutaneous secukinumab until Week 12. Patients classified as responders (achieving JIA ACR30 response) at Week 12 entered into the Part 2 double-blind phase and were randomized 1:1 to continue treatment with secukinumab or begin treatment with placebo.

Baseline Disease Characteristics

The JIA patient subtypes at study entry were: 60.5% ERA and 39.5% JPsA. In the study, 67.6% of patients with JPsA, and 63.5% of patients with ERA, were treated concomitantly with MTX.

Clinical Response

Similar responses were seen in each JIA subtype (JPsA and ERA). The JIA ACR 30, 50, 70, and 90 responses for patients with JPsA and ERA at Week 12 are presented below in Table 14.

Table 14: JIA ACR 30, 50, 70, and 90 Responses at Week 12 (Subcutaneous Treatment)
Number of subjects with response (%)	JIA ACR 30	JIA ACR 50	JIA ACR 70	JIA ACR 90
JPsA (N = 34)	31 (91)	31 (91)	24 (71)	16 (47)
ERA (N = 52)	44 (85)	41 (79)	34 (65)	17 (33)

Juvenile Psoriatic Arthritis Results

During Part 2, a total of 11 JPsA patients in the placebo group experienced a flare event compared with 4 JPsA patients in the secukinumab group. The risk of flare was reduced by 85% for patients who received secukinumab compared with patients who received placebo (Hazard Ratio = 0.15, 95% CI: 0.04 to 0.56) (Figure 5).

Figure 5: Kaplan-Meier Estimates of the Time to Disease Flare in Part 2 for JPsA Patients (Subcutaneous Treatment)

Figure 5: Kaplan-Meier Estimates of the Time to Disease Flare in Part 2 for JPsA Patients (Subcutaneous Treatment)

Enthesitis-Related Arthritis Results

During Part 2, a total of 10 ERA patients in the placebo group experienced a flare event compared with 6 ERA patients in the secukinumab group. The risk of flare was reduced by 53% for patients who received secukinumab compared with patients who received placebo (Hazard Ratio = 0.47, 95% CI: 0.17 to 1.32) (Figure 6). Supplementary analyses provided confirmatory evidence of the treatment effect in ERA.

Figure 6: Kaplan-Meier Estimates of the Time to Disease Flare in Part 2 for ERA Patients (Subcutaneous Treatment)

Figure 6: Kaplan-Meier Estimates of the Time to Disease Flare in Part 2 for ERA Patients (Subcutaneous Treatment)

14.7 Hidradenitis Suppurativa

Two randomized, double-blind, placebo-controlled 52-week Phase 3 trials (i.e., HS Trial 1 [NCT03713619] and HS Trial 2 [NCT03713632]) assessed the efficacy and safety of COSENTYX in the treatment of adult patients with moderate to severe hidradenitis suppurativa (HS). In both trials, subjects were randomized to placebo or COSENTYX 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3 and 4, followed by 300 mg every 2 weeks or every 4 weeks. At Week 16, subjects who were randomized to placebo were reassigned to receive COSENTYX 300 mg at Weeks 16, 17, 18, 19, and 20 followed by either COSENTYX 300 mg every 2 weeks (Q2W) or COSENTYX 300 mg every 4 weeks (Q4W).

Baseline Demographics and Disease Characteristics

HS Trials 1 and 2 included 1,084 adult subjects with moderate to severe HS. HS Trial 1 evaluated 541 subjects and HS Trial 2 evaluated 543 subjects, of whom 13% and 11%, respectively, received concomitant stable dose of systemic antibiotics. In HS Trial 1 and HS Trial 2, 24% and 23% of patients, respectively, were previously treated with a biologic (biologic-exposed patients) and discontinued the biologic agent for either lack of efficacy or intolerance.

Endpoints

The primary endpoint in both trials was the proportion of subjects who achieved a Hidradenitis Suppurativa Clinical Response (HiSCR50) defined as at least a 50% decrease in abscesses and inflammatory nodules (AN) count with no increase in the number of abscesses and/or in the number of draining fistulae relative to baseline at Week 16.

Clinical Response

In HS Trial 1 and HS Trial 2, a statistically significantly higher proportion of subjects treated with COSENTYX 300 mg every 2 weeks (after the first four weeks) achieved a HiSCR50 response at Week 16 compared to patients treated with placebo (see Table 15). In both HS trials, a higher proportion of subjects treated with COSENTYX 300 mg every 4 weeks (after the first four weeks) achieved HiSCR50 at Week 16 compared to subjects treated with placebo (see Table 15), where statistical significance was reached in HS Trial 2. In both trials, the onset of action of COSENTYX occurred as early as Week 2 and the efficacy progressively increased up to Week 16.

For the primary endpoint, HiSCR50, subjects who received any rescue medication or lesion intervention were considered treatment failures and handled as non-responders (n=20 in Placebo, 11 in Q4W, and 8 in Q2W in HS Trial 1; n=23 in Placebo, 17 in Q4W, and 13 in Q2W in HS Trial 2).

Improvements were seen for the primary endpoint in HS subjects regardless of previous or concomitant antibiotic treatment or previous biologic exposure.

Table 15: Clinical Response at Week 16 in Adults with Hidradenitis Suppurativa in HS Trial 1 and HS Trial 21
1Multiple imputation was implemented for missing data. 2Subjects received COSENTYX 300 mg by subcutaneous injection at Weeks 0, 1, 2, 3 and 4, followed by 300 mg every 4 weeks (Q4W) or every 2 weeks (Q2W). *Statistically significant versus placebo based on the pre-defined hierarchy with overall alpha = 0.05 (two-sided).
	HS Trial 1			HS Trial 2
	Placebo (n = 180)	COSENTYX 300 mg every 4 weeks2 (n = 180)	COSENTYX 300 mg every 2 weeks2 (n = 181)	Placebo (n = 183)	COSENTYX 300 mg every 4 weeks2 (n = 180)	COSENTYX 300 mg every 2 weeks2 (n = 180)
HiSCR50	29.4%	41.3%	44.5%*	26.1%	42.5%*	38.3%*