Key clinical-trial evidence for secukinumab

Author:Anoma Ranaweera B.V.Sc; PhD (Clinical Biochemistry, University of Liverpool, UK). Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, March 2015.


In January 2015, the US Food and Drug Administration (FDA) approved secukinumab (Cosentyx™, Novartis, USA) for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy (a drug that is absorbed into the bloodstream and distributed to all parts of the body) or phototherapy (light therapy).

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorisation for secukinumab.

Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the cytokine interleukin-17A (IL-17A) inhibiting its pro-inflammatory effects.

IL-17A is a key cytokine (messenger protein) involved in the development of plaque psoriasis, and is found in high concentrations in psoriasis plaques.

The approval of secukinumab is based on the efficacy and safety outcomes from 10 Phase II and III studies which included over 3,990 patients with moderate-to-severe plaque psoriasis. These trials included four pivotal Phase III trials, ERASURE, FIXTURE, FEATURE and JUNCTURE studies detailed below.

ERASURE study – efficacy

  • ERASURE (Efficacy of Response And Safety of two fixed secUkinumab REgimens in psoriasis) was a randomised, double-blind, placebo-controlled, multicentre, parallel-group phase III study involving 738 patients with moderate-to-severe plaque psoriasis poorly controlled with topical treatments, phototherapy, systemic therapy (methotrexate, acitretin, ciclosporin), or a combination of these therapies..
  • All patients were followed up to 52 weeks after first administration of study medication.
  • The objective of the study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area–and–severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5–point modified investigator's global assessment scale.
  • Key secondary efficacy objectives in the ERASURE study were to determine the superiority of secukinumab over placebo with respect to the proportion of patients who met the criteria for a reduction of 90% or more in the PASI score from baseline at week 12 (PASI 90); the superiority of secukinumab over placebo with respect to patient-reported psoriasis-related itching, pain, and scaling on the Psoriasis Symptom Diary at week 12; maintenance of PASI 75 from week 12 through week 52; and maintenance of a response of 0 or 1 on the modified investigator's global assessment from week 12 through week 52.
  • Authors randomly assigned 738 patients to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks up until week 48) or placebo.
  • Secukinumab was shown to be superior to placebo with respect to all the coprimary and key secondary end points (P< 0.001 vs placebo).
  • Table 1 summarises the efficacy endpoints in the ERASURE study.
Table 1
END POINT SECUKINUMAB 300MG SECUKINUMAB 150MG PLACEBO
Co-primary efficacy endpoint at week 12 – no./total no. patients (%)
PASI 75 200/245 (81.6) 174/243 (71.6) 11/246 (4.5)
Response of 0 or 1 on the modified investigator’s global assessment 160/245 (65.3) 125/244 ( (51.2) 6/246 (2.4)
Key secondary efficacy endpoints – no./total no. patients (%)
PASI 90 at week 12 145/245 (59.2) 95/243 (59.2) 3/246 (1.2)
Maintenance of PASI 75 from week 12 to week 52 161/200 (80.5) 126/174 (72.4) Not evaluated
Maintenance of 0 or 1 response on modified investigator’s global assessment from wk 12 to wk 52 119/160 (74.4) 74/125 (59.2) Not evaluated
Other efficacy endpoints – no./total no. patients (%)
PASI 100 at week 12 70/245 (28.6) 31/243 (12.8) 2/246 (0.8)
Dermatology Life Quality Index* – mean score
Baseline 13.9 13.4 12.0
Week 12 2.5 3.3 10.9
Absolute change -11.4 -10.1 -1.1
*scores on the dermatology life quality index vary from 0–30 with higher scores indicating a greater effect of disease on quality of life.

Safety – ERASURE study

  • The most common adverse events in the induction period (week 1–12) and the entire treatment period (week 1–52) in this study were nasopharyngitis, headache, and upper respiratory tract infection.
  • Adverse events from baseline to 12 weeks are summarised in Table 2.
Table2
Adverse event Secukinumab 300mg (n= 245)
No. pts (%)
Secukinumab 100mg (n = 245)
No. pts (%)
Placebo (n = 247)
No. pts (%)
Nasopharyngitis 22 (9.0) 23 (9.4) 19 (7.7)
Headache 12 (4.9) 13 (5.3) 7 (2.8)
Upper respiratory tract infections 9 (3.7) 10 (4.1) 0
Pruritus (itch) 9 (3.7) 8 (3.3) 5 (2.0)
Oropharyngeal pain 4 (1.6) 10 (4.1) 3 (1.2)
Fatigue 2 (0.8) 8 (3.3) 2 (0.8)
Hypertension 0 9 (3.7) 3 (1.2)
Influenza-like illness 5 (2.0) 3 (1.2) 3 (1.2)

FIXTURE study – efficacy

  • FIXTURE (the Full year Investigative eXamination of secukinumab vs. eTanercept Using 2 dosing Regimens to determine Efficacy in psoriasis) was a randomised, double-blind, placebo and active controlled, multicentre, parallel-group phase III study involving 1306 patients with moderate-to-severe plaque psoriasis.
  • Patients randomly assigned to secukinumab received either two 150-mg subcutaneous secukinumab injections (i.e.300 mg total) or one 150-mg injection plus one placebo injection, with both injections administered once weekly at baseline and at weeks 1, 2, 3, and 4 and then every 4 weeks until week 48.
  • Patients randomly assigned to etanercept received 50 mg administered subcutaneously twice weekly from baseline until week 12 and then once weekly through week 51, in accordance with the standard dosing regimen.
  • The placebo group received placebo injections corresponding to the secukinumab and the etanercept regimens, and the secukinumab and etanercept groups received placebo injections corresponding to the other active-drug regimen, in order to maintain a double-dummy design.
  • The objective in the FIXTURE study was to assess the superiority of secukinumab over placebo with respect to the coprimary efficacy end points of PASI 75 and a response of 0 or 1 on the modified investigator's global assessment at week 12.
  • The key secondary objectives in the FIXTURE study included assessments of the superiority of secukinumab over placebo with respect to the proportion of patients who met the criteria for PASI 90 at week 12; the superiority of secukinumab over etanercept with respect to the proportion of patients who met the criteria for PASI 75 at week 12.
  • Efficacy end points (at week 12) in FIXTURE are summarised in Table 3.
Table 3
End point Secukinumab 300mg Secukinumab 150mg Etanercept 50mg Placebo
Co-primary efficacy endpoint at week 12 – no./total no. patients (%)
PASI 75 249/323 (77.1) [P<0.001 vs etanercept and placebo] 219/327 (67.0) [P<0.001 vs etanercept and placebo] 142/323 (44.0) 16/324 (4.9)
Response of 0 or 1 on the modified investigator’s global assessment 202/323 (62.5) [P<0.001 vs etanercept and placebo] 167/327 (51.1) [P<0.001 vs etanercept and placebo] 67/323 (20.7) 5/324 (1.5)
Key secondary efficacy endpoints – no./total no. patients (%)
PASI 90 at week 12 175/323 (54.2) [P<0.001 vs etanercept] 137/327 (41.9) [P<0.001 vs etanercept] 67/323 (20.7) Not evaluated
Maintenance of PASI 75 from week 12 to week 52 210/249 (84.3) [P<0.001 vs etanercept] 180/219 (82.2)
[P = 0.009 vs etanercept] 103/142 (72.5) Not evaluated
Maintenance of 0 or 1 response on modified investigator’s global assessment from wk 12 to wk 52 161/202 (79.7) [P<0.001 vs etanercept] 113/167 (67.7) [P=0.002 vs etanercept] 50/88 (56.8] Not evaluated
Other efficacy endpoints – no./total no. patients (%)
PASI 100 at week 12 78/232 (24.1) [P <0.001 vs etanercept] 47/327 (14.4) [P <0.001 vs etanercept] 14/323 (4.3) 0/324
Dermatology Life Quality Index* – mean score
Baseline 13.3 13.4 13.4 13.4
Week 12 2.9 3.7 5.5 11.5
Absolute change -10.4 -9.7 -7.9 -1.9
*scores on the dermatology life quality index vary from 0–30 with higher scores indicating a greater effect of disease on quality of life.

Safety – FIXTURE study

The most common adverse reactions (occurring in > 2% of patients) at week 12 are summarised in table 4.

Table 4
Adverse Event
>No. pts (%)
Secukinumab 300mg
(n = 326)
Secukinumab 150mg
(n = 327)
Etanercept
(n = 323)
Placebo
(n = 327)
Nasopharyngitis 35 (10.7) 45 (13.8) 36 (11.1) 26 (8.0)
Headache 30 (9.2) 16 (4.9) 23 (7.1) 23 (7.0)
Diarrhoea 17(5.2) 12 (3.7) 11 (3.4) 6 (1.8)
Pruritus (itch) 8 (2.5) 12 (3.7) 8 (2.5) 11 (3.4)
Arthralgia (joint pain) 5 (1.5) 14 (4.3) 12 (3.7) 10 (3.1)
Upper respiratory infections 7 (2.1) 10 (3.1) 7 (2.2) 3 (0.9)
Back pain 8 (2.5) 8 (2.4) 9 (2.8) 6 (1.8)
Cough 11 (3.4) 5 (1.5) 4 (1.2) 4 (1.2)
Hypertension (high blood pressure) 5 (1.5) 10 (3.1) 5 (1.5) 4 (1.2)
Nausea 8 (2.5) 6 (1.8) 4 (1.2) 7 (2.1)
Oropharyngeal pain (pain in mouth/throat) 9 (2.8) 5 (1.5) 4 (1.2) 7 (2.1)
Infection or infestation 87 (26.7%) 101 (30.9) 79 (24.5) 63 (19.3)

FEATURE study

  • FEATURE (First study of sEcukinumAb in prefilled syringes in subjecTs with chronic plaqUe-type psoriasis REsponse) was a randomised double-blind, placebo-controlled, multicentre, phase III study involving 177 subjects with moderate-to-severe plaque psoriasis.
  • In this study, prefilled syringes (PFS) were introduced into the secukinumab clinical programme.
  • 59 patients were randomised to secukinumab 300 mg, 59 to secukinumab 150 mg, and 59 to placebo.
  • 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.
  • Safety, tolerability, and usability of secukinumab self-administration via prefilled syringe were assessed after 12 weeks.
  • 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).
  • Patients successfully self-administered treatment and reported high SIAQ (Self-Injection Assessment Questionnaire) -assessed acceptability of the pre-filled syringe throughout the trial.
  • Efficacy results (at week 12) are summarised in Table 5.
Table 5
End point Secukinumab 300mg (n = 59) Secukinumab 150mg (n = 59) Placebo (n = 59)
PASI 75 response (n %) 44 (75) 41 (69) 0
IGA of clear or almost clear (n %) 40 (68) 31 (53) 0

Adverse reactions that occurred at a higher incidence (>2%) in secukinumab-treated patients vs placebo through to week 12 included nasopharyngitis, diarrhoea and upper respiratory tract infections.

JUNCTURE study

  • JUNCTURE (Judging the efficacy of secUkinumab in patients with psoriasis using autoiNjector: a Clinical Trial evalUating treatment REsults) was a double-blind, placebo-controlled, multicentre, phase III study involving 182 subjects with moderate-to-severe plaque psoriasis.
  • In this study, the autoinjector/pen (AI) was introduced into the secukinumab clinical program.
  • 60 patients were randomised to secukinumab 300 mg, 61 to secukinumab 150 mg, and 61 to placebo.
  • Patients received subcutaneous secukinumab at weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks.
  • Safety, tolerability, and usability of secukinumab self-administration via Sensoready pen for 12 weeks were assessed.
  • 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).
  • All subjects successfully self-administered treatment without critical use-related hazards.
  • Subject acceptability of autoinjector was high throughout 12 weeks.
  • Efficacy results (at week 12) are summarised in Table 6.
Table 6
End point Secukinumab 300mg (n = 60) Secukinumab 150mg (n = 61) Placebo (n = 61)
PASI 75 response (n %) 52 (87) 43 (70) 2 (3)
IGA of clear or almost clear (n %) 44 (43) 32 (52) 0 (0)

Adverse reactions that occurred at a higher incidence (>2%) in secukinumab-treated patients vs placebo through to week 12 included nasopharyngitis, diarrhoea and upper respiratory tract infections.

Future directions for secukinumab

  • The results of these phase 3 studies validate interleukin-17A as an important therapeutic target in moderate-to-severe plaque psoriasis.
  • Responses at week 12 were sustained in the majority of patients through to week 52 with continued secukinumab therapy every 4 weeks.
  • The FIXTURE study showed the superior efficacy of secukinumab over the TNF inhibitor etanercept over a period of 52 weeks.
  • The incidences of adverse events in the secukinumab groups during induction (baseline to 12 weeks) and the entire 52-week treatment period in the FIXTURE study were similar to the incidence with etanercept.
  • However, the incidences of adverse events, notably infectious adverse events, were higher in the secukinumab groups than in the placebo group.
  • Continued vigilance with respect to the potential for candida infection will be necessary for patients undergoing treatment with interleukin-17A inhibitors.

 

Related Information

References:

On DermNet NZ:

Other websites:

Books about skin diseases:

See the DermNet NZ bookstore

Note:

The New Zealand approved datasheet is the official source of information for this prescription medicine, including approved uses and risk information. Check the New Zealand datasheet on the Medsafe website.

Note:

The New Zealand approved datasheet is the official source of information for this prescription medicine, including approved uses and risk information. Check the New Zealand datasheet on the Medsafe website.