Ixekizumab for Psoriatic Arthritis: Safety, Efficacy, and Patient Selection

Figures & data

Table 1 Treatment Emergent Adverse Events with Ixekizumab and Placebo Through 24 Weeks in People with Biologic-Naïve or TNFi-Experienced Psoriatic Arthritis

Safety Outcomes at 24 Weeks^Citation33	Placebo	IXEQ4WK	IXEQ2WK	IXE Combined
	N=224	N=229	N=225	N=454
Any infection, n(%)	62 (27.7%)	77 (33.6%)	72 (32%)	149 (32.8%)
Serious infection	0	1 (0.4%)	5 (2.2%)	6 (1.3%)
Candidiasis	1 (0.4%)	4 (1.7%)	8 (3.6%)	13 (2.6%)
Esophageal candidiasis	0	0	1 (0.4%)	1 (0.2%)
Upper respiratory infection	16 (7.1%)	16 (7.0%)	15 (6.7%)	31 (6.8%)
Nasopharyngitis	9 (4.0%)	15 (6.6%)	7 (3.1%)	22 (4.8%)
Bronchitis	7 (3.1%)	4 (1.7%)	7 (3.1%)	11 (2.4%)
Sinusitis	5 (2.2%)	9 (3.9%)	6 (2.7%)	15 (3.3%)
Urinary tract infection	5 (2.2%)	8 (3.5%)	4 (1.8%)	12 (2.6%)
Cytopenia	2 (0.9%)	2 (0.9%)	4 (1.8%)	6 (1.3%)
Hepatic events	10 (4.5%)	7 (3.1%)	11 (4.9%)	18 (4.0%)
Cerebro-cardiovascular events	2 (0.9%)	0	0	0
Depression	3 (1.3%)	4 (1.7%)	4 (1.8%)	8 (1.8%)
Malignancies (excludes NMSC)	0	2 (0.9%)	0	2 (0.4%)
Injection site reactions*	10 (4.5%)	40 (17.5%)	57 (25.3%)	97 (21.4%)
Allergic or hypersensitivity reactions**	4 (1.8%)	10 (4.4%)	14 (6.2%)	24 (5.3%)

Notes: Bold font designates statistically significant differences as calculated in the primary publications: *Injection site reactions were significantly more frequent versus placebo with both ixekizumab doses in the biologic-naïve phase III trial²³ as well as the TNFi-experienced phase III trial,²² **Allergic or hypersensitivity reactions were significantly more frequent versus placebo with both ixekizumab doses in the TNFi-experienced phase III trial.²² Up to 24 weeks, there were no deaths, no occurrence of major cardiovascular adverse events, no inflammatory bowel disease, no interstitial lung disease, no pneumocystis pneumonia, and no active or latent TB.²²,²³,³³.

Abbreviations: TEAEs, treatment emergent adverse events; NMSC, non-melanoma skin cancer; IXE, ixekizumab; IXEQ4W/IXEQ2W, ixekizumab 80 mg every 4 or every 2 weeks; ADA, adalimumab.

Table 2 Treatment Emergent Adverse Events with Ixekizumab or Adalimumab Through 24 Weeks in People with Biologic-Naïve Psoriatic Arthritis (SPIRIT-H2H)⁷,³¹

Safety Outcomes	24 Weeks^Citation7					52 Weeks^Citation31
Treatment	IXE*		ADA		p-value	IXE		ADA		p-value
	N=283		N=283			N=283		N=283
N, %	n	%	n	%		n	%	n	%
Any TEAEs	197	69.6	173	61.1	0.04	209	73.9	194	68.6	0.19
Serious AEs	10	3.5	24	8.5	0.02	12	4.2	35	12.4	<0.01
Discontinuation due to AEs	7	2.5	13	4.6	0.26	12	4.2	21	7.4	0.15
Infections	102	36.0	87	30.7	0.21	119	42.0	111	39.2	0.55
Serious infections	4	1.4	8	2.8	0.38	5	1.8	8	2.8	0.58
Candida infections	7	2.5	2	0.7	0.18	7	2.5	3	1.1	0.34
Injection site reactions	27	9.5	9	3.2	<0.01	30	10.6	10	3.5	<0.01
Allergic/hypersensitivity reactions	7	2.5	11	3.9	0.47	11	3.9	13	4.6	0.84
Cerebrocardiovascular events	3	1.1	5	1.8	0.73	5	1.8	7	2.5	0.77
Malignancies	0	0	3	1.1	-	0	0	4	1.4	-
Depression	3	1.1	7	2.5	0.34	5	1.8	9	3.2	0.42
IBD	2	0.7	0	0	-	2	0.7	0	0	-
Crohn disease	1	0.4	0	0	-	1	0.4	0	0	-
Ulcerative colitis	1	0.4	0	0	-	1	0.4	0	0	-
Cytopenias	5	1.8	11	3.9	0.20	9	3.2	12	4.2	0.66

Notes: All ixekizumab-treated participants received 160 mg loading dose upfront; 17% had moderate to severe psoriasis and received ixekizumab 80 mg every 2 weeks up to week 12 and ixekizumab 80 mg every 4 weeks thereafter; 83% without at least moderate psoriasis received ixekizumab 80 mg every 4 weeks after the initial loading dose (dosing regimens consistent with the label). Up to 24 weeks, there were no deaths, no occurrences of major cardiovascular adverse events, no inflammatory bowel disease, and no active or latent TB. P-values between adalimumab and ixekizumab were calculated using the two-sided Fisher exact test. Significant p-values (<0.05) are in bolded font.

Abbreviations: TEAEs, treatment emergent adverse events; NMSC, non-melanoma skin cancer; IXE, ixekizumab; IXEQ4W/IXEQ2W, ixekizumab 80 mg every 4 or every 2 weeks; ADA, adalimumab.

Table 3 Treatment Emergent Adverse Events in 1118 Persons with PsA Exposed to Ixekizumab for Up to 3 Years

Safety Outcomes up to 3 Years^Citation33	Ixekizumab Exposed	Ixekizumab Exposed
	(N=1118 Subjects in Total)	(%)
	Number of Subjects/People Affected Out of Total	Percentage of Subjects/People Affected Out of Total
Deaths (none were adjudicated as related to ixekizumab)	6	0.54
Major Acute Cardiovascular events	11	0.98
Fatal MACE	2	0.18
Non-fatal myocardial infarction	5	0.45
Non-fatal stroke	4	0.36
Coronary artery disease	3	0.27
Cerebrovascular accident leading to treatment discontinuation	2	0.18
Malignancy (all considered SAE and led to discontinuation of the drug)	14	1.25
Non-melanoma skin cancer	8	0.72
Breast cancer	2	0.18
Prostate cancer	1	0.09
Malignant melanoma in situ	1	0.09
Metastatic renal cell carcinoma	1	0.09
Papillary thyroid cancer	1	0.09
Upper respiratory infection	161	14.40
Nasopharyngitis	150	13.42
Injection site reactions	142	12.70
Injection site erythema	52	4.65
Injection site pain	18	1.61
Injection site reactions leading to treatment discontinuation	3	0.27
Bronchitis	81	7.25
Bronchitis categorized as serious infection	4	0.36
Candida infections	39	3.49
Esophageal candidiasis	2	0.18
Depression	29	2.59
Latent TB	19	1.70
Latent TB leading to treatment discontinuation	6	0.54
Localized herpes zoster	15	1.34
Grade 3 neutropenia <1000 and >500 PMN/mm^3	6	0.54
Cholelithiasis	5	0.45
Pneumonia categorized as serious infection	5	0.45
Pneumonia leading to treatment discontinuation	2	0.18
Bronchitis	4	0.36
Myalgia leading to treatment discontinuation	2	0.18
Adjudicated IBD with no prior history	2	0.18
Septic arthritis leading to treatment discontinuation	1	0.09
Hepatitis B leading to treatment discontinuation	1	0.09
Cellulitis leading to treatment discontinuation	1	0.09
Dermatitis leading to treatment discontinuation	1	0.09
Otitis media leading to treatment discontinuation	1	0.09
Tooth abscess leading to treatment discontinuation	1	0.09
Urinary tract infection leading to treatment discontinuation	1	0.09
Subcutaneous abscess leading to treatment discontinuation	1	0.09
Tonsillitis leading to treatment discontinuation	1	0.09

Table 4 Ixekizumab Efficacy in Biologic-Naïve Psoriatic Arthritis (SPIRIT-P1, SPIRIT-H2H)

Outcomes	PBO	IXEQ4WK		IXEQ2WK		ADA
Timeline	24 Weeks		52 Weeks	24 Weeks	52 Weeks	24 Weeks	52 Weeks
	N=106	N=107	N=191^Citation26	N=103	N=190^Citation26	N=101	–
	–	N=283	N=283	–	–	N=283	N=283
ACR20 (%)
SPIRIT-P1^Citation23,^Citation26	30.2	57.9	66.5	62.1	66.8	57.4	-
H2H^Citation7,^Citation31	–	68.9	69.6	–	–	72.1	68.9
ACR50 (%)
SPIRIT-P1^Citation23,^Citation26	15.1	40.2	52.9	46.6	48.9	38.6	–
H2H^Citation7,^Citation31	–	50.5	49.8	–	–	46.6	49.8
ACR70 (%)
SPIRIT-P1^Citation23,^Citation26	5.7	23.4	33.5	34.0	34.7	25.7	–
H2H^Citation7,^Citation31	–	31.8	35.3	–	–	25.8	34.3
PASI75 (%)
SPIRIT-P1^Citation23,^Citation26	10.34	71.2	71.0	79.7	73.5	54.4	–
H2H^Citation7,^Citation31	–	80.2		–	–	68.9
PASI90 (%)
SPIRIT-P1^Citation23,^Citation26	6.0	56.2	58.8	67.8	66.7	36.8	-
H2H^Citation7,^Citation31	–	71.7	72.8	–	–	55.8	54.1
PASI100 (%)
SPIRIT-P1^Citation23,^Citation26	3.0	42.5	48.9	52.5	55.6	23.5	–
H2H^Citation7,^Citation31	–	60.1	64.3	–	–	46.6	41.3
Enthesitis resolution, LEI=0
SPIRIT-P1^Citation23,^Citation26	19.3	42.6	51.3	38.6	42.6	33.3	-
H2H^Citation7,^Citation31	–	59.7	61.6	–	–	55.1	57.1
Dactylitis resolution, LDI=0
SPIRIT-P1^Citation23,^Citation26	25.0	79.5	81.1	76.9	75.0	77.8	–
H2H^Citation7,^Citation31	–	88.1	83.3	–	–	93.1	81.0
HAQ-DI MCID^b
SPIRIT-P1^Citation23,^Citation26	26.1	49.0	55.0	57.8	50.6	49.4	–
H2H^Citation7,^Citation31	–	66.7	66.7			65.4	64.6
Pain VAS MCIDa,^Citation32	35.6	61.2	–	71.1	–	–	–
Fatigue NRS MCIDc,^Citation32	20.4	36.8	–	40.5	–	–	–

Notes: ^aPain VAS MCID defined as ≥ 10mm/100 improvement in patients with baseline pain ≥10; ^bHAQ-DI MCID defined as improvement from baseline ≥0.35 in patients with baseline score ≥0.35; ^cFatigue NRS MCID defined as ≥3 points/10 improvement in patients with baseline fatigue score ≥3.

Abbreviations: PBO, placebo; IXE, ixekizumab; IXEQ4W/IXEQ2W, ixekizumab 80 mg every 4 or every 2 weeks; ADA, adalimumab; ACR20/50/70, 20/50/70% American College of Rheumatology responses; PASI75/90/100, 75/90/100% Psoriasis Area and Severity Index responses; LEI=0, Leeds Enthesitis Index = 0; LDI-B=0, Leeds Dactylitis Index-Basic = 0; VAS, Visual Analog Scale; MCID, Minimal Clinically important Difference; HAQ-DI, Health Assessment Questionnaire-Disability Index; NRS, Numeric Rating Scale.

Table 5 Ixekizumab Efficacy in TNFi-Experienced Psoriatic Arthritis (SPIRIT-P2)

Outcomes	PBO	IXEQ4WK		IXEQ2WK
	N=188	N=122		N=123
Timeline	24 weeks^Citation22		52 weeksa,^Citation29	24 weeks^Citation22	52 weeksa,^Citation29
ACR responses (%)
ACR20	19	53	84	48	75
ACR50	5	35	53	33	41
ACR70	0	22	32	12	20
PASI responses (%)
PASI75	15	56	81	60	83
PASI90	12	44	65	50	62
PASI100	4	35	52	28	52
Enthesitis resolution LEI=0 (%)	22	35	65	31	53
Dactylitis resolution LDI-B=0 (%)	21	75	81	50	69
HAQ-DI MCID^c (%)	17	43	60.9	40	53.8
Pain VAS MCID^b (%)^Citation32	31.6	61.9	–	55.9	–
Fatigue NRS MCID^d (%)^Citation32	5.6	30.8	–	33.6	–

Notes: ^aMultiple imputation ^bPain VAS MCID defined as ≥ 10mm/100 improvement in patients with baseline pain ≥10; ^bHAQ-DI MCID defined as improvement from baseline ≥0.35 in patients with baseline score ≥0.35; ^cFatigue NRS MCID defined as ≥3 points/10 improvement in patients with baseline fatigue score ≥3.

Abbreviations: PBO, placebo; IXE, ixekizumab; IXEQ4W/IXEQ2W, ixekizumab 80 mg every 4 or every 2 weeks; ADA, adalimumab; ACR20/50/70, 20/50/70% American College of Rheumatology responses; PASI75/90/100, 75/90/100%, Psoriasis Area and Severity Index responses; LEI=0, Leeds Enthesitis Index = 0; LDI-B=0, Leeds Dactylitis Index-Basic = 0; VAS,Visual Analog Scale; MCID, Minimal Clinically important Difference, HAQ-DI, Health Assessment Questionnaire-Disability Index; NRS, Numeric Rating Scale.

Table 6 Notable Inclusion Criteria in Clinical Trials of Ixekizumab

Inclusion Criteria	SPIRIT-P1^Citation23	SPIRIT-P2^Citation22	SPIRIT H2H^Citation7
Erosions (radiographic)	Yes (or CRP elevation), hand or foot; centrally read	Unspecified	Unspecified
Active plaque psoriasis	No	Yes	Yes
Inflammatory marker elevation (CRP>6 mg/L)	Yes (or erosions on radiography)	Unspecified	Unspecified
Prior treatment with csDMARDs	Unspecified	Yes, 1 or more	Yes, 1 or more
Prior treatment with bDMARD	No	Yes; required but limited to no more than two TNFi	No

Abbreviations: CRP, C-reactive protein; csDMARDs, classical synthetic disease modifying anti-rheumatic drugs; bDMARDs, biologic DMARDs; TNFi, tumor necrosis factor alpha inhibitor.

Table 7 Participant Baseline Characteristics in Ixekizumab Clinical Trials

Characteristic*	PBO	IXEQ4WK	IXEQ2WK	ADAQ2WK
Numbers
SPIRIT-P1^Citation23,^Citation26	N=106	N=107	N=103	N=101
H2H^Citation7,^Citation31	–	N=283	–	N=283
SPIRIT-P2^Citation40	N=118	N=122	N=123	–
Age, Mean (yrs)
SPIRIT-P1^Citation23,^Citation26	51	49	50	49
H2H^Citation7,^Citation31	–	48	–	48
SPIRIT-P2^Citation40	52	53	52	–
Women, %
SPIRIT-P1^Citation23,^Citation26	55	58	53	49
H2H^Citation7,^Citation31	–	43	–	47
SPIRIT-P2^Citation40	53	48	59	–
Weight, Mean (kg)
SPIRIT-P1^Citation23,^Citation26	84	86	82	92
H2H^Citation7,^Citation31	–	85	–	82
SPIRIT-P2^Citation40	91	90	85	–
BMI, Mean (kg/m^2)
SPIRIT-P1^Citation23,^Citation26	29	30	29	32
H2H^Citation7,^Citation31	–	30	–	30
SPIRIT-P2^Citation40	32	31	30	–
Race, %
White
SPIRIT-P1^Citation23,^Citation26	93	95	93	94
H2H^Citation7,^Citation31	–	78	–	75
SPIRIT-P2^Citation40	92	91	93	–
Asian
SPIRIT-P1^Citation23,^Citation26	5	2	5	3
H2H^Citation7,^Citation31	–	10	–	12
SPIRIT-P2^Citation40	6	6	6	–
American Indian or Alaska native
SPIRIT-P1^Citation23,^Citation26	2	2	2	3
H2H^Citation7,^Citation31	–	0	–	0
SPIRIT-P2^Citation40	0	0	0	–
Other
SPIRIT-P1^Citation23,^Citation26	0	1	0	0
H2H^Citation7,^Citation31	–	0	–	0
SPIRIT-P2^Citation40	3	3	2	–
PsA duration, Mean (yrs)
SPIRIT-P1^Citation23,^Citation26	7	6	8	8
H2H^Citation7,^Citation31	–	7	–	6
SPIRIT-P2^Citation40	7	10	7	–
Psoriasis duration, Mean (yrs)
SPIRIT-P1^Citation23,^Citation26	16	17	17	16
H2H^Citation7,^Citation31	–	13	–	13
SPIRIT-P2^Citation40	15	16	17	–
Methotrexate use, current, %
SPIRIT-P1^Citation23,^Citation26	56	53	52	56
H2H^Citation7,^Citation31	–	59	–	60
SPIRIT-P2^Citation40	34	39	50	–
Active psoriasis (%)
SPIRIT-P1^Citation23,^Citation26	96	94	92	96
H2H^Citation7,^Citation31	–	100	–	100
SPIRIT-P2^Citation40	92	97	92	–
Psoriasis ≤3%
SPIRIT-P1^Citation23,^Citation26	68	73	65	72
H2H^Citation7,^Citation31	–	100	–	100
SPIRIT-P2^Citation40	57	56	55	–
Any current nail psoriasis, %
SPIRIT-P1^Citation23,^Citation26	70	65	72	70
H2H^Citation7,^Citation31	–	68	–	63
SPIRIT-P2^Citation40	62	73	60	–
Dactylitis, current, %
SPIRIT-P1^Citation23,^Citation26	37	51	40	23
H2H^Citation7,^Citation31	–	15	–	21
SPIRIT-P2^Citation40	12	23	16
Enthesitis, current, %
SPIRIT-P1^Citation23,^Citation26	54	65	57	55
H2H^Citation7,^Citation31	–	56	–	52
SPIRIT-P2^Citation40	58	56	68	–
Swollen joint count (out of 66), Mean
SPIRIT-P1^Citation23,^Citation26	7	8	7	7
H2H^Citation7,^Citation31	–	8	–	8
SPIRIT-P2^Citation40	10	13	14	–
Tender joint count (out of 68), Mean
SPIRIT-P1^Citation23,^Citation26	13	14	14	13
H2H^Citation7,^Citation31	-	13	-	15
SPIRIT-P2^Citation40	23	22	25	-
Disability HAQ-DI, Mean
SPIRIT-P1^Citation23,^Citation26	1.2	1.2	1.2	1.1
H2H^Citation7,^Citation31	–	1.2	–	1.3
SPIRIT-P2^Citation40	1.2	1.2	1.2	–
Inflammation, CRP, Mean (mg/L)
SPIRIT-P1^Citation23,^Citation26	15	13	15	13
H2H^Citation7,^Citation31	–	10	–	11
SPIRIT-P2^Citation40	12	17	14	–

Note: *Values are rounded to the nearest whole number.

Abbreviations: PBO, placebo; IXE, ixekizumab; IXEQ4W/IXEQ2W, ixekizumab 80 mg every 4 or every 2 weeks; ADA, adalimumab; ADAQ2W, adalimumab 40 mg every 2 weeks; HAQ-DI, Health Assessment Questionnaire-Disability Index; CRP, C-reactive protein.

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