Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors
ATC code: L04AC10
Secukinumab is a fully human IgG1/κ monoclonal antibody that selectively binds to and neutralises the proinflammatory cytokine interleukin-17A (IL-17A). Secukinumab works by targeting IL-17A and inhibiting its interaction with the IL-17 receptor, which is expressed on various cell types including keratinocytes. As a result, secukinumab inhibits the release of proinflammatory cytokines, chemokines and mediators of tissue damage and reduces IL-17A-mediated contributions to autoimmune and inflammatory diseases. Clinically relevant levels of secukinumab reach the skin and reduce local inflammatory markers. As a direct consequence treatment with secukinumab reduces erythema, induration and desquamation present in plaque psoriasis lesions.
IL-17A is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. IL-17A plays a key role in the pathogenesis of plaque psoriasis, psoriatic arthritis and ankylosing spondylitis and is up-regulated in lesional skin in contrast to non-lesional skin of plaque psoriasis patients and in synovial tissue of psoriatic arthritis patients. The frequency of IL-17-producing cells was also significantly higher in the subchondral bone marrow of facet joints from patients with ankylosing spondylitis.
Serum levels of total IL-17A (free and secukinumab-bound IL-17A) are initially increased in patients receiving secukinumab. This is followed by a slow decrease due to reduced clearance of secukinumab-bound IL-17A, indicating that secukinumab selectively captures free IL-17A, which plays a key role in the pathogenesis of plaque psoriasis.
In a study with secukinumab, infiltrating epidermal neutrophils and various neutrophil-associated markers that are increased in lesional skin of plaque psoriasis patients were significantly reduced after one to two weeks of treatment.
Secukinumab has been shown to lower (within 1 to 2 weeks of treatment) levels of C-reactive protein, which is a marker of inflammation.
The safety and efficacy of secukinumab were assessed in four randomised, double-blind, placebo-controlled phase III studies in patients with moderate to severe plaque psoriasis who were candidates for phototherapy or systemic therapy [ERASURE, FIXTURE, FEATURE, JUNCTURE]. The efficacy and safety of secukinumab 150 mg and 300 mg were evaluated versus either placebo or etanercept. In addition, one study assessed a chronic treatment regimen versus a “retreatment as needed” regimen [SCULPTURE].
Of the 2,403 patients who were included in the placebo-controlled studies, 79% were biologic-naive, 45% were non-biologic failures and 8% were biologic failures (6% were anti-TNF failures, and 2% were anti-p40 failures). Approximately 15 to 25% of patients in phase III studies had psoriatic arthritis (PsA) at baseline.
Psoriasis study 1 (ERASURE) evaluated 738 patients. Patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Psoriasis study 2 (FIXTURE) evaluated 1,306 patients. Patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to etanercept received 50 mg doses twice per week for 12 weeks followed by 50 mg every week. In both study 1 and study 2, patients randomised to receive placebo who were non-responders at week 12 then crossed over to receive secukinumab (either 150 mg or 300 mg) at weeks 12, 13, 14, and 15, followed by the same dose every month starting at week 16. All patients were followed for up to 52 weeks following first administration of study treatment.
Psoriasis study 3 (FEATURE) evaluated 177 patients using a pre-filled syringe compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of secukinumab self-administration via the pre-filled syringe. Psoriasis study 4 (JUNCTURE) evaluated 182 patients using a pre-filled pen compared with placebo after 12 weeks of treatment to assess the safety, tolerability, and usability of secukinumab self-administration via the pre-filled pen. In both study 3 and study 4, patients randomised to secukinumab received 150 mg or 300 mg doses at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients were also randomised to receive placebo at weeks 0, 1, 2, 3 and 4, followed by the same dose every month.
Psoriasis study 5 (SCULPTURE) evaluated 966 patients. All patients received secukinumab 150 mg or 300 mg doses at weeks 0, 1, 2, 3, 4, 8 and 12 and then were randomised to receive either a maintenance regimen of the same dose every month starting at week 12 or a “retreatment as needed” regimen of the same dose. Patients randomised to “retreatment as needed” did not achieve adequate maintenance of response and therefore a fixed monthly maintenance regimen is recommended.
The co-primary endpoints in the placebo and active-controlled studies were the proportion of patients who achieved a PASI 75 response and IGA mod 2011 “clear” or “almost clear” response versus placebo at week 12 (see Tables 2 and 3). The 300 mg dose provided improved skin clearance particularly for “clear” or “almost clear” skin across the efficacy endpoints of PASI 90, PASI 100, and IGA mod 2011 0 or 1 response across all studies with peak effects seen at week 16, therefore this dose is recommended.
Table 2. Summary of PASI 50/75/90/100 & IGA* mod 2011 “clear” or “almost clear” clinical response in psoriasis studies 1, 3 and 4 (ERASURE, FEATURE and JUNCTURE):
Table 3. Summary of clinical response on psoriasis study 2 (FIXTURE):
In an additional psoriasis study (CLEAR) 676 patients were evaluated. Secukinumab 300 mg met the primary and secondary endpoints by showing superiority to ustekinumab based on PASI 90 response at week 16 (primary endpoint), speed of onset of PASI 75 response at week 4, and long-term PASI 90 response at week 52. Greater efficacy of secukinumab compared to ustekinumab for the endpoints PASI 75/90/100 and IGA mod 2011 0 or 1 response (“clear” or “almost clear”) was observed early and continued through to week 52.
Table 4. Summary of clinical response on CLEAR study:
Secukinumab was efficacious in systemic treatment-naive, biologic-naive, biologic/anti-TNF-exposed and biologic/anti-TNF-failure patients. Improvements in PASI 75 in patients with concurrent psoriatic arthritis at baseline were similar to those in the overall plaque psoriasis population.
Secukinumab was associated with a fast onset of efficacy with a 50% reduction in mean PASI by week 3 for the 300 mg dose.
Figure 1. Time course of percentage change from baseline of mean PASI score in study 1 (ERASURE):
In two additional placebo-controlled studies, improvement was seen in both nail psoriasis (TRANSFIGURE, 198 patients) and palmoplantar plaque psoriasis (GESTURE, 205 patients). In the TRANSFIGURE study, secukinumab was superior to placebo at week 16 (46.1% for 300 mg, 38.4% for 150 mg and 11.7% for placebo) as assessed by significant improvement from baseline in the Nail Psoriasis Severity Index (NAPSI ) for patients with moderate to severe plaque psoriasis with nail involvement. In the GESTURE study, secukinumab was superior to placebo at week 16 (33.3 for 300 mg, 22.1% for 150 mg, and 1.5% for placebo) as assessed by significant improvement of ppIGA 0 or 1 response (“clear” or “almost clear”) for patients with moderate to severe palmoplantar plaque psoriasis.
A placebo-controlled study evaluated 102 patients with moderate to severe scalp psoriasis, defined as having a Psoriasis Scalp Severity Index (PSSI) score of ≥12, an IGA mod 2011 scalp only score of 3 or greater and at least 30% of the scalp surface area affected. Secukinumab 300 mg was superior to placebo at week 12 as assessed by significant improvement from baseline in both the PSSI 90 response (52.9% versus 2.0%) and IGA mod 2011 0 or 1 scalp only response (56.9% versus 5.9%). Improvement in both endpoints was sustained for secukinumab patients who continued treatment through to week 24.
Statistically significant improvements at week 12 (studies 1-4) from baseline compared to placebo were demonstrated in the DLQI (Dermatology Life Quality Index). Mean decreases (improvements) in DLQI from baseline ranged from -10.4 to -11.6 with secukinumab 300 mg, from -7.7 to -10.1 with secukinumab 150 mg, versus -1.1 to -1.9 for placebo at week 12. These improvements were maintained for 52 weeks (studies 1 and 2).
Forty percent of the participants in studies 1 and 2 completed the Psoriasis Symptom Diary©. For the participants completing the diary in each of these studies, statistically significant improvements at week 12 from baseline compared to placebo in patient-reported signs and symptoms of itching, pain and scaling were demonstrated.
Statistically significant improvements at week 4 from baseline in patients treated with secukinumab compared to patients treated with ustekinumab (CLEAR) were demonstrated in the DLQI and these improvements were maintained for up to 52 weeks.
Statistically significant improvements in patient-reported signs and symptoms of itching, pain and scaling at week 16 and week 52 (CLEAR) were demonstrated in the Psoriasis Symptom Diary © in patients treated with secukinumab compared to patients treated with ustekinumab. Statistically significant improvements (decreases) at week 12 from baseline in the scalp psoriasis study were demonstrated in patient reported signs and symptoms of scalp itching, pain and scaling compared to placebo.
The safety and efficacy of secukinumab were assessed in 1,999 patients in three randomised, double-blind, placebo-controlled phase III studies in patients with active psoriatic arthritis (≥3 swollen and ≥3 tender joints) despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease-modifying anti-rheumatic drug (DMARD) therapy. Patients with each subtype of PsA were enrolled in these studies, including polyarticular arthritis with no evidence of rheumatoid nodules, spondylitis with peripheral arthritis, asymmetric peripheral arthritis, distal interphalangeal involvement and arthritis mutilans. Patients in these studies had a diagnosis of PsA of at least five years. The majority of patients also had active psoriasis skin lesions or a documented history of psoriasis. Over 61% and 42% of the PsA patients had enthesitis and dactylitis at baseline, respectively. For all studies, the primary endpoint was American College of Rheumatology (ACR) 20 response. For Psoriatic Arthritis study 1 (PsA study 1) and Psoriatic Arthritis study 2 (PsA study 2), the primary endpoint was at week 24. For Psoriatic Arthritis study 3 (PsA study 3), the primary endpoint was at week 16 with the key secondary endpoint, the change from baseline in modified Total Sharp Score (mTSS), at week 24.
In PsA study 1, PsA study 2 and PsA study 3, 29%, 35% and 30% of patients, respectively, were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients).
PsA study 1 (FUTURE 1) evaluated 606 patients, of whom 60.7% had concomitant MTX. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 75 mg or 150 mg subcutaneously every month starting at week 8. Patients randomised to placebo who were non-responders at week 16 (early rescue) and other placebo patients at week 24 were crossed over to receive secukinumab (either 75 mg or 150 mg subcutaneously) followed by the same dose every month.
PsA study 2 (FUTURE 2) evaluated 397 patients, of whom 46.6% had concomitant MTX. Patients randomised to secukinumab received 75 mg, 150 mg or 300 mg subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. Patients randomised to receive placebo who were non-responders at week 16 (early rescue) were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 16 followed by the same dose every month. Patients randomised to receive placebo who were responders at week 16 were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 24 followed by the same dose every month.
PsA study 3 (FUTURE 5) evaluated 996 patients, of whom 50.1% had concomitant MTX. Patients were randomised to receive secukinumab 150 mg, 300 mg or placebo subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month, or a once monthly injection of secukinumab 150 mg (without loading). Patients randomised to receive placebo who were non-responders at week 16 (early rescue) were then crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 16 followed by the same dose every month. Patients randomised to receive placebo who were responders at week 16 were crossed over to receive secukinumab (either 150 mg or 300 mg subcutaneously) at week 24 followed by the same dose every month.
Treatment with secukinumab resulted in significant improvement in measures of disease activity compared to placebo at weeks 16 and 24 (see Table 5).
Table 5. Clinical response in PsA study 2 and PsA study 3 at week 16 and week 24:
The onset of action of secukinumab occurred as early as week 2. Statistically significant difference in ACR 20 versus placebo was reached at week 3.
The percentage of patients achieving ACR 20 response by visit is shown in Figure 2.
Figure 2. ACR20 response in PsA study 2 over time up to week 52:
Similar responses for primary and key secondary endpoints were seen in PsA patients regardless of whether they were on concomitant MTX treatment or not. In PsA study 2, at week 24, secukinumab-treated patients with concomitant MTX use had a higher ACR 20 response (47.7% and 54.4% for 150 mg and 300 mg, respectively, compared to placebo 20.0%) and ACR 50 response (31.8% and 38.6% for 150 mg and 300 mg, respectively, compared to placebo 8.0%). Secukinumab-treated patients without concomitant MTX use had a higher ACR 20 response (53.6% and 53.6% for 150 mg and 300 mg, respectively, compared to placebo 10.4%) and ACR 50 response (37.5% and 32.1% for 150 mg and 300 mg, respectively, compared to placebo 6.3%).
In PsA study 2, both anti-TNFα-naive and anti-TNFα-IR secukinumab-treated patients had a significantly higher ACR 20 response compared to placebo at week 24, with a slightly higher response in the anti-TNFα-naive group (anti-TNFα-naive: 64% and 58% for 150 mg and 300 mg, respectively, compared to placebo 15.9%; anti-TNFα-IR: 30% and 46% for 150 mg and 300 mg, respectively, compared to placebo 14.3%). In the anti-TNFα-IR patients subgroup, only the 300 mg dose showed significantly higher response rate for ACR 20 compared to placebo (p<0.05) and demonstrated clinical meaningful benefit over 150 mg on multiple secondary endpoints. Improvements in the PASI 75 response were seen in both subgroups and the 300 mg dose showed statistically significant benefit in the anti-TNFα-IR patients.
The number of PsA patients with axial involvement was too small to allow meaningful assessment.
Improvements were shown in all components of the ACR scores, including patient assessment of pain. In PsA study 2, the proportion of patients achieving a modified PsA Response Criteria (PsARC) response was greater in the secukinumab-treated patients (59.0% and 61.0% for 150 mg and 300 mg, respectively) compared to placebo (26.5%) at week 24.
In PsA study 1 and PsA study 2, efficacy was maintained up to week 104. In PsA study 2, among 200 patients initially randomised to secukinumab 150 mg and 300 mg, 178 (89%) patients were still on treatment at week 52. Of the 100 patients randomised to secukinumab 150 mg, 64, 39 and 20 had an ACR 20/50/70 response, respectively. Of the 100 patients randomised to secukinumab 300 mg, 64, 44 and 24 had an ACR 20/50/70 response, respectively.
In PsA study 3, inhibition of progression of structural damage was assessed radiographically and expressed by the modified Total Sharp Score (mTSS) and its components, the Erosion Score (ES) and the Joint Space Narrowing Score (JSN). 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. Secukinumab 150 mg and 300 mg treatment significantly inhibited the rate of progression of peripheral joint damage compared with placebo treatment as measured by change from baseline in mTSS at week 24 (Table 6).
Inhibition of progression of structural damage was also assessed in PsA study 1 at weeks 24 and 52, compared to baseline. Week 24 data are presented in Table 6.
Table 6. Change in modified Total Sharp Score in psoriatic arthritis:
| PsA study 3 | PsA study 1 | ||||
|---|---|---|---|---|---|
| Placebo n=296 | secukinumab 150 mg1 n=213 | secukinumab 300 mg1 n=217 | Placebo n=179 | secukinumab 150 mg2 n=185 | |
| Total score | |||||
| Baseline (SD) | 15.0 (38.2) | 13.5 (25.6) | 12.9 (23.8) | 28.4 (63.5) | 22.3 (48.0) |
| Mean change at Week 24 | 0.50 | 0.13* | 0.02* | 0.57 | 0.13* |
* p<0.05 based on nominal, but non adjusted, p-value
1 secukinumab 150 mg or 300 mg s.c. at weeks 0, 1, 2, 3, and 4 followed by the same dose every month
2 10 mg/kg at weeks 0, 2 and 4 followed by subcutaneous doses of 75 mg or 150 mg
In PsA study 1, inhibition of structural damage was maintained with secukinumab treatment up to week 52.
In PsA study 3, the percentage of patients with no disease progression (defined as a change from baseline in mTSS of ≤0.5) from randomisation to week 24 was 80.3%, 88.5% and 73.6% for secukinumab 150 mg, 300 mg and placebo, respectively. An effect of inhibition of structural damage was observed in anti-TNFα-naïve and anti-TNFα-IR patients and in patients treated with and without concomitant MTX.
In PsA study 1, the percentage of patients with no disease progression (defined as a change from baseline in mTSS of ≤0.5) from randomisation to week 24 was 82.3% in secukinumab 10 mg/kg intravenous load – 150 mg subcutaneous maintenance and 75.7% in placebo. The percentage of patients with no disease progression from week 24 to week 52 for secukinumab 10 mg/kg intravenous load – followed by 150 mg subcutaneous maintenance and for placebo patients who switched to 75 mg or 150 mg subcutaneous every 4 weeks at week 16 or week 24 was 85.7% and 86.8%, respectively.
In PsA study 2 and PsA study 3, patients treated with secukinumab 150 mg (p=0.0555 and p<0.0001) and 300 mg (p=0.0040 and p<0.0001) showed improvement in physical function compared to patients treated with placebo as assessed by Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 24 and week 16, respectively. Improvements in HAQ-DI scores were seen regardless of previous anti-TNFα exposure. Similar responses were seen in PsA study 1.
Secukinumab-treated patients reported significant improvements in health-related quality of life as measured by the Short Form-36 Health Survey Physical Component Summary (SF-36 PCS) score (p<0.001). There were also statistically significant improvements demonstrated in exploratory endpoints assessed by the Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) scores for 150 mg and 300 mg compared to placebo (7.97, 5.97 versus 1.63, respectively) and these improvements were maintained up to week 104 in PsA study 2.
Similar responses were seen in PsA study 1 and efficacy was maintained up to week 52.
The safety and efficacy of secukinumab were assessed in 816 patients in three randomised, double-blind, placebo-controlled phase III studies in patients with active ankylosing spondylitis (AS) with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease-modifying anti-rheumatic drug (DMARD) therapy. Patients in Ankylosing Spondylitis study 1 (AS study 1) and Ankylosing Spondylitis study 2 (AS study 2) had a diagnosis of AS for a median of 2.7 to 5.8 years. For both studies, the primary endpoint was at least a 20% improvement in Assessment of Spondyloarthritis International Society (ASAS 20) criteria at week 16.
In Ankylosing Spondylitis study 1 (AS study 1), Ankylosing Spondylitis study 2 (AS study 2), and Ankylosing Spondylitis study 3 (AS study 3), 27.0%, 38.8%, and 23.5% of patients, respectively, were previously treated with an anti-TNFα agent and discontinued the anti-TNFα agent for either lack of efficacy or intolerance (anti-TNFα-IR patients).
AS study 1 (MEASURE 1) evaluated 371 patients, of whom 14.8% and 33.4% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 75 mg or 150 mg subcutaneously every month starting at week 8. Patients randomised to placebo who were non-responders at week 16 (early rescue) and all other placebo patients at week 24 were crossed over to receive secukinumab (either 75 mg or 150 mg subcutaneously), followed by the same dose every month.
AS study 2 (MEASURE 2) evaluated 219 patients, of whom 11.9% and 14.2% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 75 mg or 150 mg subcutaneously at weeks 0, 1, 2, 3 and 4, followed by the same dose every month. At week 16, patients who were randomised to placebo at baseline were re-randomised to receive secukinumab (either 75 mg or 150 mg subcutaneously) every month.
AS study 3 (MEASURE 3) evaluated 226 patients, of whom 13.3% and 23.5% used concomitant MTX or sulfasalazine, respectively. Patients randomised to secukinumab received 10 mg/kg intravenously at weeks 0, 2, and 4, followed by either 150 mg or 300 mg subcutaneously every month. At week 16, patients who were randomised to placebo at baseline were re-randomised to receive secukinumab (either 150 mg or 300 mg subcutaneously) every month. The primary endpoint was ASAS 20 at week 16. Patients were blinded to the treatment regimen up to week 52, and the study continued to week 156.
In AS study 2, treatment with secukinumab 150 mg resulted in greater improvement in measures of disease activity compared with placebo at week 16 (see Table 7).
Table 7. Clinical response in AS study 2 at week 16:
| Outcome (p-value versus placebo) | Placebo (n=74) | 75 mg (n=73) | 150 mg (n=72) |
|---|---|---|---|
| ASAS 20 response, % | 28.4 | 41.1 | 61.1*** |
| ASAS 40 response, % | 10.8 | 26.0 | 36.1*** |
| hsCRP, (post-BSL/BSL ratio) | 1.13 | 0.61 | 0.55*** |
| ASAS 5/6, % | 8.1 | 34.2 | 43.1*** |
| ASAS partial remission, % | 4.1 | 15.1 | 13.9 |
| BASDAI 50, % | 10.8 | 24.7* | 30.6** |
| ASDAS-CRP major improvement | 4.1 | 15.1* | 25.0*** |
* p<0.05, ** p<0.01, *** p<0.001; versus placebo
All p-values adjusted for multiplicity of testing based on pre-defined hierarchy, except BASDAI 50 and ASDAS-CRP
Non-responder imputation used for missing binary endpoint
ASAS: Assessment of SpondyloArthritis International Society Criteria; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; hsCRP: high-sensitivity C-reactive protein; ASDAS: Ankylosing Spondylitis Disease Activity Score; BSL: baseline
The onset of action of secukinumab 150 mg occurred as early as week 1 for ASAS 20 and week 2 for ASAS 40 (superior to placebo) in AS study 2.
ASAS 20 responses were improved at week 16 in both anti-TNFα-naïve patients (68.2% versus 31.1%; p<0.05) and anti-TNFα-IR patients (50.0% versus 24.1%; p<0.05) for secukinumab 150 mg compared with placebo, respectively.
In AS study 1 and AS study 2, secukinumab-treated patients (150 mg in AS study 2 and both regimens in AS study 1) demonstrated significantly improved signs and symptoms at week 16, with comparable magnitude of response and efficacy maintained up to week 52 in both anti-TNFα-naive and anti-TNFα-IR patients. In AS study 2, among 72 patients initially randomised to secukinumab 150 mg, 61 (84.7%) patients were still on treatment at week 52. Of the 72 patients randomised to secukinumab 150 mg, 45 and 35 had an ASAS 20/40 response, respectively.
In AS study 3, patients treated with secukinumab (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 endpoint (ASAS 20). Overall, the efficacy response rates for the 300 mg group were consistently greater compared to the 150 mg group for the secondary endpoints. During the blinded period, the ASAS 20 and ASAS 40 responses were 69.7% and 47.6% for 150 mg and 74.3% and 57.4% for 300 mg at week 52, respectively. The ASAS 20 and ASAS 40 responses were maintained up to week 156 (69.5% and 47.6% for 150 mg versus 74.8% and 55.6% for 300 mg). Greater response rates favouring 300 mg were also observed for ASAS partial remission (ASAS PR) response at week 16 and were maintained up to week 156. Larger differences in response rates, favouring 300 mg over 150 mg, were observed in anti-TNFα-IR patients (n=36) compared to anti-TNFα-naïve patients (n=114).
Patients treated with secukinumab 150 mg showed improvements in spinal mobility as measured by change from baseline in BASMI at week 16 for both AS study 1 (-0.40 versus -0.12 for placebo; p=0.0114) and AS study 2 (-0.51 versus -0.22 for placebo; p=0.0533). These improvements were sustained up to week 52.
In AS study 1 and study 2, patients treated with secukinumab 150 mg showed improvements in health- related quality of life as measured by AS Quality of Life Questionnaire (ASQoL) (p=0.001) and SF-36 Physical Component Summary (SF-36PCS) (p<0.001). Patients treated with secukinumab 150 mg also showed statistically significant improvements on exploratory endpoints in physical function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI) compared to placebo (-2.15 versus 0.68), and in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-Fatigue) scale compared to placebo (8.10 versus 3.30). These improvements were sustained up to week 52.
The European Medicines Agency has waived the obligation to submit the results of studies with Cosentyx in plaque psoriasis in paediatric patients aged from birth to less than 6 years and in chronic idiopathic arthritis for paediatric patients aged from birth to less than 2 years (see section 4.2 for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with Cosentyx in plaque psoriasis in paediatric patients aged from 6 years to less than 18 years and in chronic idiopathic arthritis for paediatric patients aged from 2 years to less than 18 years (see section 4.2 for information on paediatric use).
Most pharmacokinetics properties observed in patients with plaque psoriasis, psoriatic arthritis and ankylosing spondylitis were similar.
Following a single subcutaneous dose of 300 mg as a liquid formulation in healthy volunteers, secukinumab reached peak serum concentrations of 43.2±10.4 μg/ml between 2 and 14 days post dose.
Based on population pharmacokinetic analysis, following a single subcutaneous dose of either 150 mg or 300 mg in plaque psoriasis patients, secukinumab reached peak serum concentrations of 13.7±4.8 μg/ml or 27.3±9.5 μg/ml, respectively, between 5 and 6 days post dose.
After initial weekly dosing during the first month, time to reach the maximum concentration was between 31 and 34 days based on population pharmacokinetic analysis.
On the basis of simulated data, peak concentrations at steady-state (Cmax,ss) following subcutaneous administration of 150 mg or 300 mg were 27.6 μg/ml and 55.2 μg/ml, respectively. Population pharmacokinetic analysis suggests that steady-state is reached after 20 weeks with monthly dosing regimens.
Compared with exposure after a single dose, the population pharmacokinetic analysis showed that patients exhibited a 2-fold increase in peak serum concentrations and area under the curve (AUC) following repeated monthly dosing during maintenance.
Population pharmacokinetic analysis showed that secukinumab was absorbed with an average absolute bioavailability of 73% in patients with plaque psoriasis. Across studies, absolute bioavailabilities in the range between 60 and 77% were calculated.
The bioavailability of secukinumab in PsA patients was 85% on the basis of the population pharmacokinetic model.
The mean volume of distribution during the terminal phase (Vz) following single intravenous administration ranged from 7.10 to 8.60 litres in plaque psoriasis patients, suggesting that secukinumab undergoes limited distribution to peripheral compartments.
The majority of IgG elimination occurs via intracellular catabolism, following fluid-phase or receptor mediated endocytosis.
Mean systemic clearance (CL) following a single intravenous administration to patients with plaque psoriasis ranged from 0.13 to 0.36 l/day. In a population pharmacokinetic analysis, the mean systemic clearance (CL) was 0.19 l/day in plaque psoriasis patients. The CL was not impacted by gender. Clearance was dose- and time-independent.
The mean elimination half-life, as estimated from population pharmacokinetic analysis, was 27 days in plaque psoriasis patients, ranging from 18 to 46 days across psoriasis studies with intravenous administration.
The single and multiple dose pharmacokinetics of secukinumab in plaque psoriasis patients were determined in several studies with intravenous doses ranging from 1x 0.3 mg/kg to 3x 10 mg/kg and with subcutaneous doses ranging from 1x 25 mg to multiple doses of 300 mg. Exposure was dose proportional across all dosing regimens.
Based on population pharmacokinetic analysis with a limited number of elderly patients (n=71 for age ≥65 years and n=7 for age ≥75 years), clearance in elderly patients and patients less than 65 years of age was similar.
No pharmacokinetic data are available in patients with renal or hepatic impairment. The renal elimination of intact secukinumab, an IgG monoclonal antibody, is expected to be low and of minor importance. IgGs are mainly eliminated via catabolism and hepatic impairment is not expected to influence clearance of secukinumab.
Secukinumab clearance and volume of distribution increase as body weight increases.
Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose and reproductive toxicity, or tissue cross-reactivity.
Animal studies have not been conducted to evaluate the carcinogenic potential of secukinumab.
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