14 CLINICAL STUDIES

14.1 Treatment of CAPS

The efficacy and safety of ILARIS for the treatment of CAPS was demonstrated in CAPS Study (NCT00465985), a 3-part trial in patients 9 to 74 years of age with the MWS phenotype of CAPS. Throughout the trial, patients weighing more than 40 kg received ILARIS 150 mg and patients weighing 15 to 40 kg received 2 mg/kg. Part 1 was an 8-week open-label, single-dose period where all patients received ILARIS. Patients who achieved a complete clinical response and did not relapse by Week 8 were randomized into Part 2, a 24-week randomized, double-blind, placebo-controlled withdrawal period. Patients who completed Part 2 or experienced a disease flare entered Part 3, a 16-week open-label active treatment phase. A complete response was defined as ratings of minimal or better for physician’s assessment of disease activity (PHY) and assessment of skin disease (SKD) and had serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA) less than 10 mg/L. A disease flare was defined as a CRP and/or SAA values greater than 30 mg/L and either a score of mild or worse for PHY or a score of minimal or worse for PHY and SKD.

In Part 1, a complete clinical response was observed in 71% of patients one week following initiation of treatment and in 97% of patients by Week 8 (see Table 4 and Figure 1). In the randomized withdrawal period, a total of 81% of the patients randomized to placebo flared as compared to none (0%) of the patients randomized to ILARIS. The 95% confidence interval for treatment difference in the proportion of flares was 53% to 96%. At the end of Part 2, all 15 patients treated with ILARIS had absent or minimal disease activity and skin disease (see Table 4).

In a second trial (NCT00465985), patients 4 to 74 years of age with both MWS and FCAS phenotypes of CAPS were treated in an open-label manner. Treatment with ILARIS resulted in clinically significant improvement of signs and symptoms and in normalization of high CRP and SAA in a majority of patients within 1 week.

Table 4: Physician’s Global Assessment of Auto Inflammatory Disease Activity and Assessment of Skin Disease: Frequency Table and Treatment Comparison in Part 2 (Using LOCF, ITT Population)
		ILARIS N = 15		Placebo N = 16
	Baseline	Start of Part 2 (Week 8)	End of Part 2		Start of Part 2 (Week 8)	End of Part 2
Physician's Global Assessment of Auto Inflammatory Disease Activity – n (%)
Absent	0/31 (0)	9/15 (60)	8/15 (53)	8/16 (50)		0/16 (0)
Minimal	1/31 (3)	4/15 (27)	7/15 (47)	8/16 (50)		4/16 (25)
Mild	7/31 (23)	2/15 (13)	0/15 (0)	0/16 (0)		8/16 (50)
Moderate	19/31 (61)	0/15 (0)	0/15 (0)	0/16 (0)		4/16 (25)
Severe	4/31 (13)	0/15 (0)	0/15 (0)	0/16 (0)		0/16 (0)
Assessment of skin disease – n (%)
Absent	3/31 (10)	13/15 (87)	14/15 (93)		13/16 (81)	5/16 (31)
Minimal	6/31 (19)	2/15 (13)	1/15 (7)		3/16 (19)	3/16 (19)
Mild	9/31 (29)	0/15 (0)	0/15 (0)		0/16 (0)	5/16 (31)
Moderate	12/31 (39)	0/15 (0)	0/15 (0)		0/16 (0)	3/16 (19)
Severe	1/32 (3)	0/15 (0)	0/15 (0)		0/16 (0)	0/16 (0)

Markers of inflammation CRP and SAA normalized within 8 days of treatment in the majority of patients. Normal mean CRP (Figure 1) and SAA values were sustained throughout CAPS Study 1 in patients continuously treated with canakinumab. After withdrawal of canakinumab in Part 2, CRP (Figure 1) and SAA values again returned to abnormal values and subsequently normalized after reintroduction of canakinumab in Part 3. The pattern of normalization of CRP and SAA was similar.

Figure 1. Mean C-Reactive Protein Levels at the End of Parts 1, 2, and 3 of CAPS Study 1

Figure 1. Mean C-Reactive Protein Levels at the End of Parts 1, 2, and 3 of CAPS Study 1

14.2 Treatment of Periodic Fever Syndromes: TRAPS, HIDS/MKD, and FMF

The efficacy and safety of ILARIS for the treatment of TRAPS, HIDS/MKD, and FMF was demonstrated in a 4-Part study (TRAPS, HIDS/MKD, and FMF Study 1) (NCT02059291) consisting of three separate, disease cohorts (TRAPS, HIDS/MKD, and FMF) which enrolled 185 patients aged greater than 28 days. Patients in each cohort entered a 12-week screening period (Part 1) during which they were evaluated for the onset of disease flare. Patients aged 2 to 76 years were then randomized at flare onset into a 16-week double-blind, placebo-controlled treatment period (Part 2) where they received either 150 mg ILARIS (2 mg/kg for patients weighing less than or equal to 40 kg) subcutaneously or placebo every 4 weeks. Part 3 and Part 4 of this study are ongoing.

Randomized patients in Part 2 treated with ILARIS whose disease flare did not resolve, or who had persistent disease activity from Day 8 up to Day 14 (Physician’s Global Assessment [PGA] greater than or equal to 2 or C-reactive Protein [CRP] greater than 10 mg/L and no reduction by at least 40% from baseline) received an additional dose of 150 mg (or 2 mg/kg for patients weighing less than or equal to 40 kg). Patients treated with ILARIS whose disease flare did not resolve, or who had persistent disease activity from Day 15 up to Day 28 (PGA greater than or equal to 2 or CRP greater than 10 mg/L and no reduction by at least 70% from baseline), also received an additional dose of 150 mg (or 2 mg/kg for patients weighing less than or equal to 40 kg). On or after Day 29, patients treated with ILARIS in Part 2 with PGA greater than or equal to 2 and CRP greater than or equal to 30 mg/L were also up-titrated. All up-titrated patients remained at the increased dose of 300 mg (or 4 mg/kg for patients weighing less than or equal to 40 kg) every 4 weeks.

The primary efficacy endpoint of the randomized, 16-week treatment period (Part 2) was the proportion of complete responders within each cohort as defined by patients who had resolution of their index disease flare at Day 15 and did not experience a new disease flare during the remainder of the 16-week treatment period. Resolution of the index disease flare (initial flare at the time of the randomization) was defined at the Day 15 visit as a PGA Disease Activity score less than 2 (“minimal or no disease”) and C-reactive Protein (CRP) within normal range (less than or equal to 10 mg/L) or reduction greater than or equal to 70% from baseline. The key signs and symptoms assessed in the PGA for each condition were the following: TRAPS: abdominal pain, skin rash, musculoskeletal pain, eye manifestations; HIDS/MKD: abdominal pain; lymphadenopathy, aphthous ulcers; FMF: abdominal pain, skin rash, chest pain, arthralgia/arthritis. A new flare was defined as a PGA score greater than or equal to 2 (“mild, moderate, or severe disease”) and CRP greater to or equal than 30 mg/L. In the 16-week treatment period (Part 2), patients who needed dose escalation, who crossed over from placebo to ILARIS, or who discontinued from the study due to any reason prior to Week 16 were considered as non-responders.

Patients randomized in the TRAPS cohort (N = 46) were aged 2 to 76 years (median age at baseline: 15.5 years) and of this population, 57.8% did not have fever at baseline. Randomized TRAPS patients were those with chronic or recurrent disease activity defined as 6 flares per year (median number of flares per year: 9.0) with PGA greater than or equal to 2 and CRP greater than 10 mg/L (median CRP at baseline: 112.5 mg/L). In the TRAPS cohort, 11/22 (50.0%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 21/24 (87.5%) patients randomized to placebo crossed over to ILARIS.

Patients randomized in the HIDS/MKD cohort (N = 72) were aged 2 to 47 years (median age at baseline: 11.0 years) and of this population, 41.7% did not have fever at baseline. Randomized HIDS/MKD patients were those with a confirmed diagnosis of HIDS according to known genetic MVK/enzymatic (MKD) findings, and documented prior history of greater than or equal to 3 febrile acute flares within a 6-month period (median number of flares per year: 12.0) when not receiving prophylactic treatment and during the study, had active HIDS flares defined as PGA greater than or equal to 2 and CRP greater than 10 mg/L (median CRP at baseline: 113.5 mg/L). In the HIDS/MKD cohort, 19/37 (51.4%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 31/35 (88.6%) patients randomized to placebo crossed over to ILARIS.

Patients randomized in the FMF cohort (N = 63) were aged 2 to 69 years (median age at baseline: 18.0 years) and of this population, 76.2% did not have fever at baseline. Randomized FMF patients were those with documented active disease despite colchicine therapy or documented intolerance to effective doses of colchicine. Patients had active disease defined as at least one flare per month (median number of flares per year: 18.0) and CRP greater than 10 mg/L (median CRP at baseline: 94.0 mg/L). Patients were allowed to continue their stable dose of colchicine without change. Of the 63 randomized patients, 55 (87.3%) were taking concomitant colchicine therapy on or after randomization. In the FMF cohort, 10/31 (32.3%) patients randomized to ILARIS 150 mg every 4 weeks received up-titration to 300 mg every 4 weeks during the 16-week treatment period, while 27/32 (84.4%) patients randomized to placebo crossed over to ILARIS.

For the primary efficacy endpoint, ILARIS was superior to placebo in the proportion of TRAPS, HIDS/MKD, and FMF patients who resolved their index disease flare at Day 15 and had no new flare over the 16 weeks of treatment from the time of the resolution of the index flare (see Table 5).

Table 5: Proportion of TRAPS, HIDS/MKD, and FMF Patients Who Achieved a Complete Response (Resolution of Index Flare by Day 15 and Maintained Through Week 16)
	ILARIS 150 mg	Placebo	Treatment comparison
Cohort	n/N (%)	n/N (%)	Odds ratio 95% CI	p-value
TRAPS	10/22 (45.5%)	2/24 (8.3%)	9.17 (1.51, 94.61)	0.005
HIDS/MKD	13/37 (35.1%)	2/35 (5.7%)	8.94 (1.72, 86.41)	0.002
FMF	19/31 (61.3%)	2/32 (6.3%)	23.75 (4.38, 227.53)	<0.0001
Abbreviation: CI, confidence interval. n = number of patients with the response. N = number of patients evaluated for that response in each cohort.

At Day 15, a higher proportion of ILARIS-treated patients compared to placebo-treated patients experienced resolution of their index flare in all disease cohorts (see Table 6).

Table 6: Resolution of Index Flare (Full Analysis Set)
	Resolution at Day 15*
	ILARIS 150 mg every 4 weeks	Placebo
Variable	n/N (%)	n/N (%)
TRAPS	14/22 (63.6%)	5/24 (20.8%)
HIDS/MKD	24/37 (64.9%)	13/35 (37.1%)
FMF	25/31 (80.7%)	10/32 (31.3%)
n = number of patients with the response. N = number of patients evaluated for that response in each cohort. *Resolution of index disease flare (PGA less than 2 and CRP less than or equal to 10 mg/L or reduction greater than or equal to 70% from baseline).

There was supportive evidence of efficacy for ILARIS at Day 15, as compared to placebo, for the components of the primary endpoint, CRP and PGA Disease Activity score, as well as for the secondary endpoint SAA level (see Table 7).

Table 7: Proportion of TRAPS, HIDS/MKD, and FMF Patients Achieving PGA Less Than 2, CRP Less Than or Equal to 10 mg/L and SAA Less Than or Equal to 10 mg/L at Day 15*
	TRAPS			HIDS/MKD			FMF
Variable	ILARIS 150 mg	Placebo	Treatment comparison	ILARIS 150 mg	Placebo	Treatment comparison	ILARIS 150 mg	Placebo	Treatment comparison
	n/N (%)	n/N (%)	Odds ratio 95% CI	n/N (%)	n/N (%)	Odds ratio 95% CI	n/N (%)	n/N (%)	Odds ratio 95% CI
PGA less than 2	14/22 (63.6%)	8/24 (33.3%)	4.06 (1.12, 14.72)	26/37 (70.3%)	14/35 (40.0%)	3.42 (1.28, 9.16)	27/31 (87.1%)	13/32 (40.6%)	10.07 (2.78, 36.49)
CRP less than or equal to 10 mg/L	13/22 (59.1%)	8/24 (33.3%)	3.88 (1.05, 14.26)	25/37 (67.6%)	9/35 (25.7%)	6.05 (2.14, 17.12)	28/31 (90.3%)	9/32 (28.1%)	22.51 (5.41, 93.62)
SAA less than or equal to 10 mg/L	7/22 (31.8%)	2/24 (8.3%)	5.06 (0.92, 27.91)	10/37 (27.0%)	4/35 (11.4%)	2.94 (0.82, 10.53)	13/31 (41.9%)	5/32 (15.6%)	3.73 (1.11, 12.52)
Abbreviation: CI: confidence interval. n = number of patients with the response. N = number of patients evaluated for that response in each cohort. *ILARIS-treated patients who up-titrated or discontinued prior to Day 15 and placebo-treated patients who switched over to ILARIS or discontinued prior to Day 15 were classified as nonresponders.

14.3 Treatment of Still’s Disease: AOSD and SJIA

SJIA

The efficacy of ILARIS for the treatment of active SJIA was assessed in 2 Phase 3 studies (SJIA Study 1 and SJIA Study 2). Patients enrolled were aged 2 to less than 20 years (mean age at baseline: 8.5 years) with a confirmed diagnosis of SJIA at least 2 months before enrollment (mean disease duration at baseline: 3.5 years). Patients had active disease defined as greater than or equal to 2 joints with active arthritis (mean number of active joints at baseline: 15.4), documented spiking, intermittent fever (body temperature greater than 38°C) for at least 1 day within 1 week before study drug administration, and CRP greater than 30 mg/L (normal range less than 10 mg/L) (mean CRP at baseline: 200.5 mg/L). Patients were allowed to continue their stable dose of methotrexate, corticosteroids, and/or NSAIDs without change, except for tapering of the corticosteroid dose as per study design in SJIA Study 2 (see below).

SJIA Study 1 (NCT00886769) was a randomized, double-blind, placebo-controlled, single-dose 4-week study assessing the short-term efficacy of ILARIS in 84 patients randomized to receive a single subcutaneous dose of 4 mg/kg ILARIS or placebo (43 patients received ILARIS and 41 patients received placebo). The primary objective of this study was to demonstrate the superiority of ILARIS versus placebo in the proportion of patients who achieved at least 30% improvement in an adapted pediatric American College of Rheumatology (ACR) response criterion which included both the pediatric ACR core set (ACR30 response) and absence of fever (temperature less than or equal to 38°C in the preceding 7 days) at Day 15.

Pediatric ACR responses are defined by achieving levels of percentage improvement (30%, 50%, and 70%) from baseline in at least 3 of the 6 core outcome variables, with worsening of greater than or equal to 30% in no more than one of the remaining variables. Core outcome variables included a physician global assessment of disease activity, parent or patient global assessment of well-being, number of joints with active arthritis, number of joints with limited range of motion, CRP, and functional ability (Childhood Health Assessment Questionnaire-CHAQ).

Percentages of patients by pediatric ACR response are presented in Table 8.

Table 8: Pediatric ACR Response at Days 15 and 29
	Day 15			Day 29
	ILARIS	Placebo	Weighted Difference1 (95% CI)2	ILARIS	Placebo	Weighted difference1 (95% CI)2
	N = 43	N = 41		N = 43	N = 41
ACR30	84%	10%	70% (56%, 84%)	81%	10%	70% (56%, 84%)
ACR50	67%	5%	65% (50%, 80%)	79%	5%	76% (63%, 88%)
ACR70	60%	2%	64% (49%, 79%)	67%	2%	67% (52%, 81%)
1Weighted difference is the difference between the ILARIS and placebo response rates, adjusted for the stratification factors (number of active joints, previous response to anakinra, and level of oral corticosteroid use). 2CI = confidence interval for the weighted difference. N = Number of patients.

Results for the components of the pediatric ACR core set were consistent with the overall ACR response results, for systemic and arthritic components, including the reduction in the total number of active joints and joints with limited range of motion. Among the patients who returned for a Day 15 visit, the mean change in patient pain score (0 to 100 mm visual analogue scale) was -50.0 mm on ILARIS (N = 43), as compared to +4.5 mm on placebo (N = 25). The mean change in pain score among ILARIS-treated patients was consistent through Day 29. All patients treated with ILARIS had no fever at Day 3 compared to 87% of patients treated with placebo.

SJIA Study 2 (NCT00889863) was a randomized, double-blind, placebo-controlled, withdrawal study of flare prevention by ILARIS in patients with active SJIA. Flare was defined by worsening of greater than or equal to 30% in at least 3 of the 6 core Pediatric ACR response variables combined with improvement of greater than or equal to 30% in no more than 1 of the 6 variables, or reappearance of fever not due to infection for at least 2 consecutive days. The study consisted of 2 major parts: 177 patients were enrolled in the study and received 4 mg/kg ILARIS subcutaneously every 4 weeks in Part I and 100 of these patients continued into Part II to receive either ILARIS 4 mg/kg or placebo subcutaneously every 4 weeks.

Corticosteroid Dose Tapering

Of the total 128 patients taking corticosteroids who entered the open-label portion of Study 2, 92 attempted corticosteroid tapering. Fifty-seven (62%) of the 92 patients who attempted to taper were able to successfully taper their corticosteroid dose and 42 (46%) discontinued corticosteroids.

Time to Flare

Part II was a randomized withdrawal design to demonstrate that the time to flare was longer with ILARIS than with placebo. Follow-up stopped when 37 events had been observed resulting in patients being followed for different lengths of time. The probability of experiencing a flare over time in Part II was statistically lower for the ILARIS treatment group than for the placebo group (Figure 2). This corresponded to a 64% relative reduction in the risk of flare for patients in the ILARIS group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75).

Figure 2. Kaplan-Meier Estimates of the Probability to Stay Flare-Free in Part II of SJIA Study 2 by Treatment (ILARIS (ACZ885) and Placebo groups)

Figure 2. Kaplan-Meier Estimates of the Probability to Stay Flare-Free in Part II of SJIA Study 2 by Treatment (ILARIS (ACZ885) and Placebo groups)

Very few patients were followed for more than 48 weeks.

AOSD

The efficacy of ILARIS in adults with AOSD is based on the pharmacokinetic exposure and extrapolation of the established efficacy of ILARIS in SJIA patients. Efficacy of ILARIS was also assessed in a randomized, double-blind, placebo-controlled study that enrolled 36 patients (22 to 70 years old) diagnosed with AOSD. The efficacy data were generally consistent with the results of a pooled efficacy analysis of SJIA patients.

14.4 Treatment of Gout Flares

The efficacy of ILARIS was demonstrated in two 12-week, randomized, double-blind, active-controlled studies in patients with gout flares for whom NSAIDs and/or colchicine were contraindicated, not tolerated or ineffective, and who had experienced at least three gout flares in the previous year (Studies 1 and 2). The studies continued in 1) two 12-week, double-blind, active-controlled extensions, followed by 2) two open-label extensions and continued 3) in a third open-label extension (combined for both studies) up to a maximum of 36 months where all patients were treated with ILARIS upon a new flare.

In Study 1 (NCT01029652), patients were randomized to receive ILARIS 150 mg subcutaneous (N = 115) or triamcinolone acetonide 40 mg intramuscular (N = 115) at baseline and thereafter treated upon a new flare. Two patients randomized to canakinumab were not included in the analysis as they did not receive any study medication. In Study 2 (NCT01080131), patients were randomized to receive ILARIS 150 mg subcutaneous (N =112) or triamcinolone acetonide 40 mg intramuscular (N =114) at baseline and thereafter treated upon a new flare.

In Studies 1 and 2, over 85% of patients had at least one co-morbidity, including hypertension (60%), obesity (53%), diabetes (15%), and ischemic heart disease (12%). Twenty-five percent of patients had chronic kidney disease (stage ≥ 3), based on eGFR. Concomitant treatment with allopurinol or other uric acid lowering therapies was reported by 42% of patients at entry.

The majority of patients (73%) reported between 3-6 flares in the year prior to study entry and the remainder reported seven or more flares. Approximately one-third of the patients enrolled [76 in the ILARIS group (33.5%) and 84 in the triamcinolone acetonide (36.7%) group] had documented inability (intolerance, contraindication or lack of response) to use both, NSAIDs and colchicine. The remainder had intolerance, contraindication or lack of response to either NSAIDs or colchicine.

In both studies, the co-primary endpoints were: (i) patient’s assessment of gout flare pain intensity at the most affected joint at 72 hours post-dose measured on a 0-100 mm visual analogue scale (VAS) and (ii) the time to first new gout flare. The studies aimed to determine whether ILARIS 150 mg would be superior to triamcinolone acetonide 40 mg.

Study 3 (NCT01356602), an additional 12-week, randomized, double-blind, active-controlled study, enrolled 397 patients with ILARIS 150 mg subcutaneous (Pre-Filled Syringe (PFS), N=133, Lyophilizate (LYO), N=132) or triamcinolone acetonide 40 mg intramuscular (N=132). Eight patients (2 ILARIS PFS, 3 ILARIS LYO, 3 triamcinolone) were not included for efficacy assessment as they did not receive study medication. Pain intensity at the most affected joint, assessed on a 0-100 mm VAS at 72-hours post-dose was the primary endpoint, and time to first new gout flare was a secondary endpoint. Approximately 44% of patients (45.9% ILARIS PFS group, 47.4%, ILARIS LYO group and 40.6% in the triamcinolone acetonide group) were unable to use NSAIDs and colchicine (due to contraindications, intolerance, or inadequate response) in this study.

Analyses of both endpoints were conducted for Studies 1, 2, and 3 for the subpopulation of patients unable to use NSAIDs and colchicine (due to contraindications, intolerance, or inadequate response) and overall population of patients unable to use NSAIDs and/or colchicine.

Efficacy on Pain

In all studies (Study 1, 2, and 3), pain intensity of the most affected joint (0-100 mm VAS) at 72 hours post-dose was consistently lower for patients treated with ILARIS compared with triamcinolone acetonide in the subpopulation of patients unable to use NSAIDs and colchicine as shown in Table 9, and Figure 3 (Study 3). This benefit of ILARIS on pain intensity was comparable to the overall patient populations i.e., patients unable to use NSAIDs and/or colchicine in all three studies (see Table 9).

Table 9: Pain Intensity of the Most Affected Joint at 72-h post treatment
Study	Population	ILARIS 150 mg		Triamcinolone acetonide 40 mg		Difference (95% CI)* in Pain Intensity 72 Hours Post-dose VAS (0-100 mm): ILARIS vs. Triamcinolone acetonide
		N	Mean (SE)*	N	Mean (SE)*
Study 1	Patients unable to use NSAIDs and colchicine	22	21.4 (6.05)	37	38.4 (4.65)	-17.0 mm (-32.3, -1.6)
	Patients unable to use NSAIDs and/or colchicine	113	27.9 (2.42)	115	39.7 (2.40)	-11.8 mm (-18.5, -5.1)
Study 2	Patients unable to use NSAIDs and colchicine	53	24.1 (3.32)	44	33.1 (3.65)	-9.1 mm (-18.9, 0.8)
	Patients unable to use NSAIDs and/or colchicine	112	21.9 (2.31)	114	31.7 (2.29)	-9.8 mm (-16.2, -3.4)
Study 3	Patients unable to use NSAIDs and colchicine	62	20.8 (3.11)	51	40.3 (3.42)	-19.5 mm (-28.6, -10.3)
		60#	18.5 (3.16)			-21.8 mm (-31.0, -12.6)
	Patients unable to use NSAIDs and/or colchicine	129	19.7 (2.05)	129	32.4 (2.05)	-12.7 mm (-18.4, -7.0)
		131#	17.0 (2.04)			-15.4 mm (-21.1, -9.8)
Abbreviation: CI = confidence interval; SE=Standard Error #Prefilled Syringe (PFS) formulation. *Adjusted mean, standard error for mean and difference between treatment groups are estimated based on analysis of covariance (ANCOVA) model with treatment, baseline VAS score and baseline BMI as covariates. For Study 3, the use of urate lowering therapy (Yes/No) at baseline is also included in the model as additional covariate. N = number of patients randomized and received at least one dose of study treatment.

Figure 3. Pain Intensity Over Time in the Subpopulation of Patients Unable to Use NSAIDs and Colchicine (Study 3, ILARIS (ACZ885) 150mg)

Figure 3. Pain Intensity Over Time in the Subpopulation of Patients Unable to Use NSAIDs and Colchicine (Study 3, ILARIS (ACZ885) 150mg)

Time to New Flare

In the subpopulation of patients in Studies 1, 2 and 3 unable to use NSAIDs and colchicine, time to new flare over 12 weeks from randomization showed a reduction in the risk of a new flare when treated with ILARIS compared with triamcinolone acetonide 40 mg (see Table 10).

This risk reduction for a new flare after ILARIS treatment versus triamcinolone acetonide was comparable to the overall patient population over 12 weeks in all 3 studies (see Table 10).

Table 10: Time to New Flare Over the 12 Weeks From Randomization
Study	Population	ILARIS 150 mg		Triamcinolone acetonide 40 mg		Risk reduction for a new flare ILARIS vs. Triamcinolone acetonide Hazard ratio# (95% CI)
		N	Flare rate*(n)	N	Flare rate*(n)
Study 1	Patients unable to use NSAIDs and colchicine	22	14% (3)	38	46% (17)	75% 0.25 (0.07, 0.85)
	Patients unable to use NSAIDs and/or colchicine	113	19% (21)	115	37% (40)	55 % 0.45 (0.26 to 0.76)
Study 2	Patients unable to use NSAIDs and colchicine	54	16% (8)	46	43% (19)	72% 0.28 (0.12, 0.65)
	Patients unable to use NSAIDs and/or colchicine	112	14% (15)	114	38% (42)	68% 0.32 (0.18 to 0.58)
Study 3	Patients unable to use NSAIDs and colchicine	62	10% (6)	51	32% (15)	71% 0.29 (0.11, 0.74)
		60#	3% (2)			91% 0.09 (0.02, 0.41)
	Patients unable to use NSAIDs and/or colchicine	129	10% (12)	129	44% (52)	82% 0.18 (0.10, 0.34)
		131#	9% (12)			83% 0.17 (0.09, 0.33)
Abbreviation: CI = confidence interval. #Prefilled Syringe (PFS) formulation. * Flare rates up to 12 weeks are estimated using Kaplan-Meier method; n = number of patients with new flares. The risk reduction and hazard ratio between treatment groups are estimated using Cox proportional hazard (Cox-PH) model with treatment and baseline BMI as covariates. For study 3, the use of urate lowering therapy (Yes/No) at baseline is also included in the model as additional covariate. N = number of patients randomized and received at least one dose of study treatment.