Treatment challenges in the management of moderate-to-severe plaque psoriasis – role of secukinumab

Figures & data

Table 1 Secukinumab Phase III trials efficacy and safety

Trial	Design	PASI 75 at week 12	PASI 90 at week 12	PASI 100 at week 12	Conclusion
FIXTURE (2011–2013), Langley et al,^Citation26 52 weeks, N=1,306	Arms: secukinumab 300 mg (S300) or secukinumab 150 mg (S150) S300 vs S150 (weekly injections then monthly) vs etanercept (E) (50 mg 2×/wk for 12 weeks then 1×/wk until week 48) vs PL MC, DB, PG, PC, R	S300 – 77.1% S150 – 67% E – 44% PL – 4.9% P<0.0001	S300 – 54.2% S150 – 41.9% E – 20.7% PL – 1.5% P<0.0001	S300 – 24.1% S150 – 14.4% E – 4.3% PL – 0% P<0.0001	Secukinumab was superior to etanercept and placebo up through week 52
	AEs:
	Common: nasopharyngitis, headache, URI, diarrhea
	Any AEs rates similar in induction phase between all groups
	Any AEs, maintenance phase, per 100 patient-years: 252 in S300, 236.4 in S150, 243.3 in E, and 329.7 in PL
	Similar AE rates between secukinumab and etanercept: no apparent differences in types of SAEs
	Serious infections per 100 patient-years: 1.1 in S300, 0.6 in S150, 1.2 in E, and 0.3 in PL
	Malignancy per 100 patient-years: 0.6 in S300, 0.4 in S150, 0.6 in E, and 0.3 in PL
	3 MACE events: 1 CVA and 1 MI (same subject) in S150 group and 1 MI in PL group
	Less injection site reactions than etanercept
	Candida infections: S300 4.7% (mild to moderate), S150 2.3% (mild to moderate), E 1.2% (two had severe infections)
	Grades 1 and 2 neutropenia. Grade 3 neutropenia in one patient (also while on PL)
	1 unrelated death due to suicide during the screening process
	ADA were found in 4 of 980 patients, none were neutralizing
ERASURE (2011–2013), Langley et al,^Citation26 52 weeks, N=738	Arms: S300 vs S150 vs PL Weekly for 1 month then monthly injections until week 48 MC, DB, PG, PC, R	S300 – 81.6% S150 – 71.6% PL – 4.5% P<0.0001	S300 – 59.2% S150 – 39.1% PL – 1.2% P<0.0001	S300 – 28.6% S150 – 12.8% PL – 0.8% P<0.0001	Secukinumab 300 mg dose is superior to the secukinumab 150 mg dose Both were superior to placebo
	AEs:
	Any AEs, incidence rate per 100 subject-years: 245 in S300, 269 in S150, and 323 in PL
	SAE incidence low, comparable among all groups:
	Increased incidence of mild to moderate infections/infestations in secukinumab groups. Only dose related in candida infections
	Serious infections per 100 patient-years: 1 for S300, 0.7 for S150, and 1.5 for PL
	4 MACE events: 2 CVAs and 2 MIs in the secukinumab groups
	Malignancy incidence per 100 subject-years: 0.3 for S300, 2 for S150, and 1.5 for PL
	11 candida infections (oral, genital, mild to moderate): S300: 7, S150: 3, PL: 1
	Grades 1 and 2 neutropenia. 1 subject with Grade 3 neutropenia which first occurred while on PL
	No deaths
	Two of 703 developed ADA, none were neutralizing
ERASURE (2011–2013) subanalysis, Ohtsuki et al,^Citation38 Japanese population, 52 weeks, N=87	Arms: S300 vs S150 vs PL Injections at weeks 1, 2, 3, 4 then monthly until week 48 MC, DB, PG, PC, R	S300 – 82.8% S150 – 86.2% PL – 6.9% P<0.0001 for both doses	S300 – 62.1% S150 – 55.2% PL – 0% P<0.0001 for both doses	S300 – 27.6% S150 – 10.3% PL – 0% P<0.01 for 300 mg dose	Maximum reduction in PASI was seen at week 16 Efficacy of secukinumab was sustained to week 52 Over time, secukinumab 300 mg showed superior efficacy over 150 mg dose especially with higher thresholds PASI 90/100
	AE:
	Patients with AE (number of patients/number of arm) induction: 14/29 in S300, 16/29 in S150, and 12/29 in PL
	Patients with AE, maintenance, per 100 patient-years: 199.7 for S300, 290.7 for S150, 223.1 for PL
	SAEs: pulmonary edema and heart failure (S150), DM2 (S150), pneumonia (S300), and aortic thrombosis/aneurysm (S150)
	No deaths
	No ADAs in the Japanese population
JUNCTURE (2012–2013), Paul et al,^Citation23 12 weeks, N=182	Self-injection with autoinjector/pen: S300 vs S150 vs PL MC, DB, PG, R	S300 – 86.7% S150 – 71.7% PL – 3.3%P<0.0001	S300 – 55% S150 – 40% PL – 0% P<0.0001	S300 – 26.7% S150 – 16.7% PL – 0% P<0.0006	The autoinjector makes it easy for patients to safely and confidently self inject. The autoinjector needle is hidden and is activated by simply placing the cap against the skin
	AE:
	Any AE, number of patients/number of arm: 42/60 in S300, 39/61 in S150, and 33/61 in PL
	SAE: 1 in S300, 2 in S150, and 1 in PL
	A case of serious pneumonia and malignant melanoma in situ reported unrelated to study drug
	No MACE
	1 vulvovaginal and 1 oral candidiasis, mild infections
	Neutropenia in 5% of S300, 8.2% of S150, and 3.3% in PL, Grade 1 or 2
	No deaths
	No ADA antibodies
SCULPTURE (2011–2013), Mrowietz et al,^Citation20 52 weeks, N=966, multicenter, double-blinded parallel group	S300 and S150 Fixed regimen (every 4 weeks, FR) vs retreat as needed (RN) (received treatment to week 12 followed by PL until loss of 20% of maximum PASI score or loss of PASI 75 response) MC, DB, PG, R	PASI 75 at week 12: S300–90.1% S150–84.4% Maintenance of PASI 75 at Week 40/52: S300 RN – 67.7%; S150 RN – 52.4% S300 FR – 78.2%; S150 FR – 62.1% Mantel–Haenszel risk difference with 98.75 confidence used to determine noninferiority analysis			Regular 4 weeks dosing of secukinumab or the fixed regimen is more efficacious for maintenance therapy
	AE rates were similar between all treatment arms (no placebo arm in this trial)
	Most common AEs: nasopharygnitis, headache, URI
	SAE rates were similar in induction phase
	SAE rates in maintenance phase: 14 S300 RN, 18 S300 FR, 13 S150 RN, 12 S150 FR
	Two MACE events – acute MI and fatal cerebral hemorrhagic stroke (study investigator: unrelated)
	One death due to CVA
	Six total neoplasms
	13 candida infections, all mild to moderate oral or genital candidiasis
	Grade 3 neutropenia in 7 patients, transient no serious infections association
	About four of 966 patients had ADAs. Two were neutralizing but not associated with decreased efficacy or pharmacokinetic abnormalities
FEATURE (2012–2013), Blauvelt et al,^Citation24 12 weeks, N=177, multicenter, double-blinded parallel group	Evaluation of self-injection with prefilled syringes (PFS) S300 vs S150 vs PL PFS MC, DB, PG, PC, R	S300 – 75.9% S150 – 69.5% PL – 0% P<0.0001%	S300 – 60.3% S150 – 52.5% PL – 0% P<0.0001	S300 – 43.1% (P<0.0001) S150 – 8.5% (P<0.057) PL – 0%	Good tolerability of self-injections with PFS. The PFS has a spring that reveals then needle once the injector is pressed down
	AEs:
	Any AE, similar among groups (number of patients/number of arm): 30/59 in S300, 34/59 in S150, and 28/59 in PL
	SAEs: 3 in S300, 0 in S150, and 1 in PL, sciatica and exfoliative dermatitis + 2 MACE
	Severe infections: 3 cases, 1:1:1 in S300, S150, and PL
	Two MACE events: CVA and MI in patients with multiple cardiac risk factors prior to starting the study
	No deaths
	Three cases of mild to moderate vulvovaginal candidiasis in S300 and S150
	Grade 1 neutropenia in 5%–9% of patients, 1 patient with Grade 2 neutropenia. None of these patients had serious infections
CLEAR (2014), Thaci et al,^Citation25 52 weeks, N=676	S300 mg vs ustekinumab (dosing per protocol) MC, DB, PG, PC, R	Week 12: S300 – 91 Ustekinumab – 79.1 P=0.0003 Week 16: S300 – 93.1 Ustekinumab – 82.1 P=0.0001%	Week 12: S300 – 72.8 Ustekinumab – 53.4 P<0.0001% Week 16: S300 – 79 Ustekinumab – 57.6 P<0.0001%	Week 12: S300 – 38.9 Ustekinumab – 25.7 P<0.0001% Week 16: S300 – 44.3 Ustekinumab – 28.4 P<0.0001%	Secukinumab is superior to ustekinumab in efficacy and comparable in safety
	AEs:
	Any AE, similar between S300 (62%) vs ustekinumab (58%) (no placebo arm)
	Mild to moderate infections were most common 29% S300 and 25% ustekinumab.
	SAEs 10 in S300 and 10 in ustekinumab groups
	Three MACE: 1 unstable angina, 1 MI, and 1 embolic stroke (dosing groups/drug not listed)
	One malignancy: lung adenocarcinoma
	One injection site reaction – nausea/vomiting
	Two hepatic: transaminitis while on INH
	Three serious infections: appendicitis, diverticulitis, and scrotal abscess
	No deaths
	Candida infections: twelve cases mild, oral, or genital mucocutaneous infections, localized
	Ten cases of oral herpes
	No neutropenia, IBD, or tuberculosis

Abbreviations: MC, multicenter; R, randomized; DB, double-blinded; PG, parallel grouped; PC, placebo-controlled; AE, adverse events; PL, placebo; SAE, serious adverse events; MACE, major adverse cardiac events; CVA, cerebrovascular accident; MI, myocardial infarction; INH, isoniazid; IBD, inflammatory bowel disease; ADAs, antidrug antibodies; URI, upper respiratory tract infection; wk, week; PASI, Psoriasis Area and Severity Index.

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