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Real‐world evidence of secukinumab in psoriasis treatment – a meta‐analysis of 43 studies – Augustin – 2020 – Journal of the European Academy of Dermatology and Venereology

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Introduction and objectives

Plaque psoriasis (PsO) is a chronic inflammatory condition, which necessitates long‐term management to achieve optimal responses. Secukinumab is a fully human monoclonal antibody that selectively neutralizes IL‐17A, the key cytokine involved in the development of PsO.1, 2 Secukinumab has shown long‐lasting efficacy and safety in the complete spectrum of psoriatic manifestations, including nails, scalp, palms and soles, and psoriatic arthritis (PsA).1-4 This has primarily been demonstrated through phase II5, 6 and phase III randomized controlled trials,1, 7, 8 which led to the licence approval of secukinumab in the treatment of moderate‐to‐severe PsO by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) in 2015.9 Since its licence approvals, investigators have published several real‐world evidence (RWE) studies in secukinumab from key national registries and an increasing number of independent real‐world studies.

The introduction of secukinumab and other biologics now allows patients with chronic PsO to be treated with long‐term therapy. RWE studies on secukinumab have demonstrated its long‐term effectiveness, accompanied by high and similar drug survival rates as TNF inhibitors (TNFi). Along with secukinumab, ustekinumab and TNFi are the only other biologic agents which have amassed sufficient RWE data for meta‐analyses studies.10, 11

With a paradigm shift towards biologic maintenance therapy, it is vital to assimilate accurate, reliable long‐term information from secukinumab‐treated patients in the real‐world setting. Of particular interest is drug survival, the rate and duration of adherence to a given biologic; this represents its long‐term effectiveness, safety and real‐world utility.12 Drug survival depends on a number of factors including flexibility of dosing regimen, drug administration, prior exposure to biologics, comorbidities, reimbursement criteria and introduction of new drugs to the market.13 Some evidence has indicated that after an initial period of high efficacy, clinical responses of biologics may decline over time,14 thus leading to treatment discontinuation.15, 16

In everyday clinical practice, heterogeneity exists between patients (differences in disease severity and comorbidities) and healthcare systems (clinical guidelines and local management of chronic conditions); thus, a carefully controlled meta‐analysis can provide valuable insights from unselected patient populations in the real world, which differ from those investigated under the stringent conditions of a controlled trial.

The aim of the current meta‐analysis was to conduct a rigorous review of all available published literature and ongoing studies that included adult moderate‐to‐severe PsO patients treated with secukinumab. Studies included RWE cohort studies, prospective and retrospective studies, case series, or letters to evaluate evidence on the effectiveness, drug survival and safety of secukinumab.

Materials and methods

Search strategy

Two databases, EMBASE (https://www.embase.com) and ClinicalTrials.gov (https://clinicaltrials.gov), were searched. EMBASE was searched using prespecified inclusion criteria and combinations of key words for PsO patient populations and study designs (Table 1). The analysis included studies from 1 January 2015 to 31 May 2019. Conference abstracts were also identified via EMBASE but no separate search was conducted for individual conferences. Retrieved records were screened for real‐world studies that reported the outcomes of interest: drug survival, Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), Physician Global Assessment (PGA) and safety results. The ClinicalTrials.gov website was also searched for ongoing observational studies with secukinumab in patients with moderate‐to‐severe PsO. Ongoing studies or those completed in the last 2 years were included. Additionally, internal publications (mainly meeting abstracts) from Novartis were included in the meta‐analysis.

Table 1.
Inclusion criteria and study designs/setting included in the meta‐analysis
Inclusion criteria Study designs/setting included
  • Effectiveness of secukinumab treatment
  • Registry (country‐specific registries)
  • Treatment pre‐ and at least 3 months postsecukinumab
  • Moderate‐to‐severe psoriasis patients (as defined by European Union/US FDA label)
  • Adult patients (≥18 years)
  • English language
  • Human subjects
  • Cohort studies
  • Case–control studies
  • Case series, case reports or letters
  • Real‐world evidence/real‐life clinical practice monitoring
  • Observational
  • Non‐interventional
  • Prospective/retrospective

The analysis included publications from the same registry, study centre or cohort, which reported different outcome(s) in different publications, or those that reported the same outcome(s), but at different time intervals [3 months (12 weeks), 6 months (24 or 26 weeks) and 12 months (48 or 52 weeks)] with the same or different sample sizes. There was a low possibility that some duplicate studies were included due to the reporting of summary level data in certain reports. To account for this, we performed a sensitivity analysis of all included studies, which demonstrated no skew in the conclusions (data on file).

Outcome measures

Outcome measures included data on secukinumab drug survival, effectiveness and safety from baseline to 3, 6 and 12 months unless otherwise stated. The outcome measures recorded the following: drug survival of secukinumab recorded the percentage of patients who remained on secukinumab treatment; treatment discontinuation recorded the percentage of patients who discontinued secukinumab treatment due to lack of efficacy/effectiveness, from baseline to 12 months; PASI 75, 90 and 100 recorded the percentage of responders who achieved a 75%, 90% and 100% reduction in PASI score; PASI (continuous variable) recorded the change in score; PGA score recorded the percentage of patients achieving a clear (0) or almost clear (1) score; DLQI score recorded the percentage of patients reaching a minimal clinically important difference with a decrease of ≥5; DLQI (continuous variable) recorded change in score; and safety endpoints recorded the percentage of patients who had any adverse event (AE). PASI, PGA and DLQI were all calculated for patients who were still on secukinumab treatment at that time. At all outcomes, mean difference (MD) and 95% confidence intervals (CI) were measured.

Statistical analysis

The analysis was carried out using a meta‐package and R statistical software (version 3.4.1; https://www.r-project.org). Presecukinumab measurements were used as a control to compare to the same patient. An inverse variance (IV) with a random effects analysis model was employed, and the effect measure was reported as MD with 95% CI for continuous variables. Single‐point proportions were analysed using Mantel–Haenszel (MH) tests with a random effects analysis model, and the effect measure was reported as risk difference with 95% CIs. Further changes in the proportions of patients with particular outcomes (presecukinumab vs. 3, 6 and 12 months of treatment) were reported as risk ratios with MH as the statistical method and a random effects analysis model.

To address clinical heterogeneity across RWE studies, a random effects analysis model was used. In all analyses, a P value of <0.05 (two‐tailed test) was considered statistically significant.

The analysis included all single‐arm secukinumab studies and the secukinumab arm of comparator studies. The analysis compared differences in symptoms between presecukinumab use vs. postsecukinumab use at 3, 6 and 12 months. Treatment comparisons were not analysed. No imputation method was used if data were missing for any study; however, clinical study reports were assessed to capture the missing data, if available.

Results

This meta‐analysis includes 43 studies that met the prespecified criteria (Table 1) out of 513 records, as shown in the PRISMA flow diagram in Fig. 1. All cited studies are included in Table 2.

image

PRISMA flow diagram. n , number of publications; PRISMA , Preferred Reporting Items for Systematic Reviews and Meta‐Analyses.

Table 2.
Publications included in the meta‐analysis
First author Publication title Sample size
Arevalo (2017) Analysis of efficacy and safety of secukinumab in patients with moderate to severe psoriasis in clinical practice39 17
Augustin (2018) Development, validation and implementation of an international Real‐World‐Evidence (RWE) database for psoriasis40 275
Bagel (2018) Secukinumab clinical and patient‐reported outcomes after 1 year of follow‐up: real‐world analyses from the Corrona Psoriasis Registry41 306
Bagel (2019) Secukinumab significantly improves disease severity and patient ‐reported outcomes up to 1 year of follow‐up: real world analyses from the corrona psoriasis registry42 306
Egeberg (2018) Safety, efficacy and drug survival of biologics and biosimilars for moderate‐to‐severe plaque psoriasis30 195
Egeberg (2019) Drug survival of secukinumab and ixekizumab for moderate‐to‐severe plaque psoriasis16 368
Ferrières (2019) Long‐term maintenance of secukinumab in psoriasis: association with patient profile and initial psoriasis clearance43 91
Galluzzo (2018) Secukinumab in moderate‐to‐severe plaque psoriasis: a multi‐center, retrospective, real‐life study up to 52 weeks observation22 107
Garcia Martin (2018) Secukinumab for the treatment of moderate to severe plaque psoriasis and psoriatic arthritis in clinical practice28 32
Georgakopoulos (2017) Efficacy and safety of secukinumab (IL‐17A inhibitor) in treating moderate to severe plaque psoriasis in real‐world clinical practice: A Canadian multicenter retrospective study44 47
Georgakopoulos (2018) Drug survival of secukinumab in real‐world plaque psoriasis patients: a 52‐week, multicenter, retrospective study45 41
Ger (2019) Effectiveness and safety of secukinumab for psoriasis in real‐world practice: analysis of subgroups stratified by prior biologic failure or reimbursement46 118
Gisondi (2019) Efficacy of secukinumab without the initial weekly loading dose in patients with chronic plaque psoriasis47 156
Ho (2018) Secukinumab demonstrates improvement of disease activity in Canadian psoriasis patients in a real world setting48 3020
Lee (2018) Drug survival of secukinumab for psoriasis in a real‐world setting19 48
López Jiménez (2019) Secukinumab vs. ustekinumab for skin clearance in patients with moderate to severe psoriasis after a year of treatment: Real‐world practice49 29
Lunder (2019) Drug survival of biological therapy is showing class effect: updated results from Slovenian National Registry of psoriasis50 165
Lynde (2018) Secukinumab treated patients in the PURE registry (Patients with moderate to severe chronic plaqUe psoRiasis in Latin AmErica and Canada): 12 month follow‐up data51 305
Malagoli (2018) Secukinumab for the treatment of residual psoriasis: a case series52 12
Megna (2019) Effectiveness and safety of secukinumab in Italian patients with psoriasis: an 84 week, multicenter, retrospective real‐world study53 324
Moron (2019) Effectiveness and safety of secukinumab in patients with moderate to severe plaque psoriasis54 33
Notario (2018) Treatment of patients with plaque psoriasis with secukinumab in a real‐life setting: a 52‐week, multicenter, retrospective study in Spain55 136
Ortiz (2018) 5PSQ‐027 Early real‐world effectiveness and safety of secukinumab in patients with psoriasis29 60
Ortiz Salvador (2019) A prospective multi‐center study assessing effectiveness and safety of secukinumab in a real‐life setting in 158 patients56 158
Papp (2017) Secukinumab treated patients in the PURE registry (Patients with moderate to severe chronic plaqUe psoRiasis in Latin AmErica and Canada): 6‐month follow‐up data23 186
Papp (2018) Secukinumab treated patients in the PURE registry (Patients with moderate to severe chronic plaqUe psoRiasis in Latin AmErica Canada and (LACan)): 18 month follow up data57 397
Papp (2019) Secukinumab treatment results in improvement of disease characteristics in patients with moderate to severe psoriasis: 24 month follow‐up data from the PURE Registry58 490
Phoon (2016) A novel anti‐IL 17a therapy in treatment of moderate to severe psoriasis in Singapore59 13
Phung (2017) Effectiveness and safety of off‐label secukinumab dosing regimens for the treatment of moderate‐to severe plaque psoriasis in adult patients: a retrospective multicentre study60 6
Poulin (2018) Secukinumab demonstrates significant improvement of disease activity and health related quality of life in Canadian psoriasis patients in a real world setting61 2216
Rubio (2017) Efficacy and safety of secukinumab in moderate to severe plaque psoriasis62 11
Schwensen (2017) Effectiveness and safety of secukinumab in 69 patients with moderate to severe plaque psoriasis: A retrospective multicenter study27 69
Sears (2019) Clinical outcomes in patients on secukinumab (Cosentyx) within a specialist psoriasis clinic: a single centre, retrospective cohort study63 35
Sotiriou (2018) Secukinumab survival and long‐term efficacy in patients with plaque psoriasis: real‐life data from a tertiary hospital in Greece64 42
Strober (2017) Secukinumab improves clinical and patient reported outcomes in psoriasis patients in a real world setting: results from the Corrona Psoriasis Registry65 96
Strober (2017) Disease characteristics, clinical and patient reported outcomes in psoriasis patients treated with secukinumab in a US real‐world setting: effectiveness results from the Corrona Psoriasis Registry66 47
Strober (2019) US real‐world effectiveness of secukinumab for the treatment of psoriasis: 6‐month analysis from the Corrona Psoriasis Registry21 306
Szlumper (2017) Clinical outcomes in patients on secukinumab within a tertiary‐referral, specialist psoriasis clinic: a single‐centre, retrospective cohort36 35
Thaci (2018) Secukinumab real‐world effectiveness data on plaque psoriasis treatment in Germany corroborate pivotal clinical trial results: Analysis of the first 2000 subjects enrolled in the PROSPECT study67 1692
Torres (2019) Secukinumab drug survival in patients with psoriasis: a multicenter, real‐world, retrospective study17 330
Tsentemeidou (2019) Real‐life efficacy and safety of secukinumab: results from a tertiary hospital in Greece68 42
Van den Reek (2018) Initial results of secukinumab drug survival in patients with psoriasis: a multicentre daily practice cohort study69 196
Yanofsky (2019) Secukinumab demonstrates significant improvement of disease activity and health related quality of life at 1 year in Canadian psoriasis patients in a real world setting70 3448

Drug survival results

At 3 months, secukinumab drug survival was 90% [total number of patients combined (N ) = 902, six studies, 95% CI 0.82–0.97]. At 6 months, drug survival was 90% (N  = 1080, five studies, 95% CI 0.83–0.97; Fig. 2). Pooled analysis from 16 studies at 12 months showed secukinumab drug survival was 80% (N  = 4691, 95% CI 0.75–0.85).

image

Secukinumab drug survival at 3, 6 and 12 months. CI , confidence interval; MH , Mantel–Haenszel.

The number of patients who discontinued secukinumab treatment due to lack of effectiveness was 8% (N  = 1125, eight studies, 95% CI 0.06–0.14, P  < 0.01) at 12 months.

Effectiveness results

The percentage of patients who achieved PASI 75 vs. baseline was 72% at 3 months (N  = 1299, 14 studies, 95% CI 0.62–0.81), 79% at 6 months (N  = 1847, 10 studies, 95% CI 0.70–0.87) and 80% at 12 months (N  = 1276, 14 studies, 95% CI 0.72–0.88). The percentage of patients who achieved PASI 90 vs. baseline was 50% at 3 months (N  = 1218, 11 studies, 95% CI 0.36–0.63), 53% at 6 months (N  = 1808, eight studies, 95% CI 0.43–0.64) and 60% at 12 months (N  = 1180, 12 studies, 95% CI 0.51–0.69). The percentage of patients who achieved PASI 100 vs. baseline was 36% at 3 months (N  = 461, five studies, 95% CI 0.15–0.56), 46% at 6 months (N  = 1196, five studies, 95% CI 0.24–0.68) and 51% at 12 months (N  = 349, six studies, 95% CI 0.31–0.72; Fig. 3a–c).

image

Psoriasis area and severity index (a) 75, (b) 90 and (c) 100 at 3, 6 and 12 months. CI , confidence interval; MH , Mantel–Haenszel.

Patients achieved significant reductions (P  < 0.01 for all) in PASI total scores vs. baseline at 3 months (N  = 156 for pre‐ and postsecukinumab, one study, MD −10.15, 95% CI −10.95 to −9.35), 6 months (N  = 1870 for presecukinumab and N  = 1299 for postsecukinumab, three studies, MD −13.11, 95% CI −17.66 to −8.55) and 12 months (N  = 599 for both pre‐ and postsecukinumab, three studies, MD −13.25, 95% CI −15.74 to −10.76; data not shown).

The percentage of patients who achieved a PGA score of 0 or 1 was 55% at 3 months (N  = 76, two studies, 95% CI 0.09–1.01), 100% at 6 months (N  = 6, one study, 95% CI 0.73–1.27) and 68% at 12 months (N  = 41, one study, 95% CI 0.54–0.83).

The percentage of patients who achieved a DLQI 0/1 was 57% at 3 months (N  = 275, one study, 95% CI 0.51–0.63), 55% at 6 months (N  = 710, three studies, 95% CI 0.50–0.61) and 65% at 12 months (N  = 434, two studies, 95% CI 0.60–0.69) of secukinumab treatment (Fig. 4). After 6 months (N  = 1067 for presecukinumab and N  = 793 for postsecukinumab, four studies, MD −8.98, 95% CI −11.63 to −6.32) and 12 months (N  = 539 for pre‐ and postsecukinumab, three studies, MD −10.96, 95% CI −14.96 to −6.96) of secukinumab treatment, a significant reduction (P  < 0.01) was observed in DLQI score vs. baseline.

image

Proportion of patients with a dermatology life quality index 0/1 at 3, 6 and 12 months. CI , confidence interval; MH , Mantel–Haenszel.

Safety results

Data on safety results were available from 14 studies (N  = 1226) that ranged in duration from 3 to 24 months. Results showed that the proportion of patients who experienced AEs was consistent with rates experienced in randomized controlled trials, and no new safety signals were observed.

Conclusions

A large and growing body of evidence has accumulated on the use of secukinumab in the treatment of moderate‐to‐severe PsO since its approval in 2015, which has enabled the publication of several RWE studies. Secukinumab, ustekinumab and TNFi are the only biologic agents that have amassed sufficient evidence for such meta‐analysis studies. This robust report of 43 RWE studies on secukinumab provides data on drug survival, effectiveness and safety measures.

Drug survival, the rate and duration of adherence to secukinumab, was of particular interest in this meta‐analysis because it provides important insights into the long‐term effectiveness, safety and real‐world utility.12 In our meta‐analysis, we report that 80% of patients continued secukinumab treatment until 12 months, consistent with the observed rates in other RWE reports.17 As demonstrated by an independent RWE meta‐analysis,18 the secukinumab drug survival rate closely mirrors that of ustekinumab (82%) and is higher than the 1‐year survival rates for etanercept (66%), adalimumab (69/%) and infliximab (61%).18 One publication by Lee et al .19 appeared to be an outlier and demonstrated a lower drug survival rate for secukinumab compared with the other publications in this meta‐analysis. A relatively small sample size of 48 patients was included in this publication. Additionally, two pronounced differences existed in the baseline characteristics of patients who ‘survived’ secukinumab treatment and those who ‘failed’ secukinumab treatment (defined, in this report, as adding on oral medication/phototherapy or switching to a different oral/biologic agent); these included a history of three or more previous biologics (10% vs. 25%, respectively), and patients with concurrent PsA (10% vs. 35.7%, respectively). The authors concluded it was possible that the patient population included in their report represented a difficult‐to‐treat population. In clinical practice, drug survival can be influenced by many factors, including previous exposure to biologics or other psoriasis treatments, comorbidities, AEs, and patient’s weight and body mass index.15, 20 However, evidence has shown that loss of efficacy over time plays a prime role in a patient’s decision to abandon a particular treatment, which is especially true for all biologics.15

Consistent with phase III clinical trials, secukinumab has demonstrated effective and rapid clinical improvement and long‐term maintenance in the treatment of moderate‐to‐severe PsO in the real world, as demonstrated through the improvement of PASI scores.21, 22 In our analysis, 80% of patients achieved PASI 75 and over half of patients remaining on secukinumab treatment achieved complete resolution of symptoms (PASI 100) by 12 months. Although these results should not be directly compared to clinical trial results due to differences in analysis methods used, these rates are, in fact, slightly higher than those reported in the ERASURE trial for PASI 75 and PASI 100 (75% and 40%, respectively).1 This could be explained by patient variations, analysis techniques or simply due to chance. The PASI 75 scores reported at 3 months in this RWE meta‐analysis are slightly lower than those achieved in phase III clinical trials, which is not unexpected because real‐world analyses include a heterogeneous patient population rather than the highly controlled populations commonly included in trials.

Similarly, patient‐reported outcomes for quality of life improved in a significant (P  < 0.01) number of patients vs. their baseline scores, indicating that results observed in clinical practice are similar to those reported in phase III clinical trials.23

In this analysis, we did not specifically investigate the effect of secukinumab in relation to previous treatments, but some reports indicate that rates of drug survival are higher for biologic‐naive patients vs. biologic‐experienced patients.17 Interestingly, as many as 61% of patients in the PURE registry (Patients with moderate‐to‐severe chronic plaqUe psoRiasis in Latin AmErica and Canada) had previously been treated with another biologic and 19% had a history of PsA.24 Twelve‐month results from this registry show that the percentage of patients with a DLQI score ≤1 was 46%, and this did not differ between biologic‐naive (46%) and biologic‐experienced patients (47%).25 Often, patients who are treated with secukinumab have tried and failed one or more other biologic agents.26 Some of the studies included in our meta‐analysis demonstrate that secukinumab is effective and well tolerated in patients who are refractory to other biologics,27-29 and may therefore offer a new treatment avenue in this patient population.

It is important to evaluate RWE alongside data from clinical trials because real‐world studies provide valuable insights into a specific condition within unselected patient populations in daily clinical practice. The general nature of RWE means that niche populations are included, such as very young or old patients, who would not meet clinical trial inclusion criteria. For example, the DERMBIO registry30 included several patients who had previously received ≥4 biologic treatments before commencing secukinumab treatment; some clinical studies would exclude such patients. Evidence compiled from real‐world practice is useful for treating physicians to help them understand long‐term effectiveness and safety of a particular therapy, adherence to treatment guidelines, drug prescription patterns and cost‐effectiveness.31

Comorbidities can negatively influence the ability to achieve complete skin clearance (PASI 100)22 as well as drug survival rates.32 Evidence has shown that many patients with PsO experience comorbidities, such as PsA,33 anxiety and depression,34 and cardiovascular disease.35 Indeed, baseline comorbidities were present in patients in some of the RWE studies included in this analysis,23, 36 although not all studies reported baseline characteristics. Secukinumab was found to be effective in patients with significant comorbidities who had failed previous biologic therapy, including ustekinumab.36 Secukinumab has emerged as one of the preferred biologic agents to manage chronic psoriasis in patients with multiple comorbidities, including PsA, obesity and congestive heart failure.37

Overall, safety events were low and consistent with clinical trial data. No new or unexpected safety signals were observed from the 14 (N  = 1226) studies for which safety data were available. Most AEs reported were similar to those seen in previous studies and in line with AEs from the 5‐year extension study involving patients with moderate‐to‐severe psoriasis.38 Few of the publications that reported safety data included comparator agents and when they did, the cohorts were not always well matched, and thus, it is difficult to draw meaningful conclusions from these data. We recommend that further RWE studies are conducted to specifically investigate the long‐term safety of secukinumab.

Our meta‐analysis is limited by potential bias as only published studies and registry data are included, and some failed uses of secukinumab may not have been reported in the literature. As review publications were included, there is also potential bias of incomplete retrieval of results within specific reports. Additionally, the meta‐analysis presented is only from the single arm of studies; we did not analyse the comparative effectiveness vs. other biologic therapies as too few studies were available for this. Additionally, there was variation between the studies regarding the methods of analysis used (some implemented imputation analysis, whereas others did not), thus introducing a source of inconsistency between data reporting.

The outcome of this meta‐analysis strengthens the body of evidence that already exists for the use of secukinumab in the treatment of patients with moderate‐to‐severe PsO, supporting clinical trial findings and reinforcing its high levels of effectiveness and good tolerance.

Acknowledgements

The authors would like to thank Craig Richardson of Novartis Pharmaceuticals for his guidance and support, and Gillian Brodie of Novartis Pharmaceuticals Ireland for medical writing support, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

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