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  1. 1. Secukinumab demonstrates high efficacy and a favourable safety profile in paediatric patients with severe chronic plaque psoriasis: 52-week results from a Phase 3 double-blind randomized, controlled trial DOI: 10.1111/jdv.17002 Received: 20 July 2020; revised: 23 September 2020; Accepted: 14 October 2020
  2. 2. Introduction • Psoriasis is a chronic inflammatory condition characterized bywell-defined red plaques with silver or white scales that are itchy and vary in severity • Psoriasis affects 2–4% of the adult population in the western countries with a worldwide prevalence rangingfrom 0.91% to 8.5%. • The prevalence of childhoodpsoriasis varies depending on the study population and is reported to be 1.3–2.1% in Europe and 0.13% in the USA. Paediatric psoriasis is more common after puberty (0.6–1.3%) than before puberty (0.1–0.5%) • Although psoriasis can arise at any age, the median age of onset of paediatric psoriasis is between 7 and 10 years • Treatment for paediatric psoriasis has expanded in recent years with approval of tumour necrosis factor (TNF)-a inhibitors, IL-12/23 inhibitor and IL-17A inhibitor for varying disease severity
  3. 3. • Secukinumab is a fully human monoclonal antibody that selectively neutralizes IL-17A, a cornerstone cytokine involved in the pathogenesis of psoriatic disease • Secukinumab has been recently approved by the European Commission (July, 2020) for the treatment of moderate-to-severe plaque psoriasis in children and adolescents from the age of 6 years who are candidates for systemic therapy • Study wasdesigned to evaluate the efficacy and safety of secukinumab in children and adolescents (aged 6 to <18 years) • The efficacy and safety of two secukinumab dosing regimens [low (LD) and high dose (HD)] in paediatric patients with severe chronic plaque psoriasis over one year are reported
  4. 4. Materials and methods • Study design • This was a global, multicentre, randomized, double-blind placebo-and active-controlled (etanercept in single-blinded arm) study in paediatric patients aged 6 years to <18 years with severe chronic plaque psoriasis. Patients were randomized using a 1 : 1 : 1 : 1 ratio into one of the treatment arms: secukinumab low dose (LD), secukinumab high dose (HD), etanercept or placebo • Patients randomized to secukinumab treatment arms (HD and LD) received a dose based on their weight category (<25 kg, 25 to <50 kg, ≥50 kg): patients weighing ≥50 kg received 150 mg (LD group) or 300 mg (HD group), those weighing 25 to <50 kg received 75 mg (LD group) or 150 mg (HD group), and patients weighing <25 kg received 75 mg for both dose groups. • Patients in the etanercept arm received weekly subcutaneous dose of 0.8 mg/kg (up to a maximum of 50 mg) of etanercept
  5. 5. • The study consisted of five periods: • Screening period (of up to 4 weeks): to assess the eligibility of the patients and to allow a drug-free washout period • Induction period (randomization to Week 12): During this time, the study was both active- and placebo-controlled and the co-primary endpoints (PASI 75 and IGA mod 2011 0 or 1 response) were assessed at Week 12. At the randomization visit, patients randomized to the placebo group were pre- assigned to either LD or HD secukinumab, in case they did not achieve a Psoriasis Area Severity Index (PASI) 75 response at Week 12. Placebo PASI 75 responders at Week 12, terminated their treatment and entered the posttreatment follow-up period • The maintenance period (Week 12 to Week 52): During this time, the study was active-controlled and the objectives focused on the maintenance of the response observed at Week 12. Patients who received secukinumab or etanercept during induction continued with the same treatment. Etanercept patients terminated their treatment at Week 52 andentered the treatment-free follow-up period. Patients who were on placebo treatment during induction period and were PASI 75 non-responders at Week 12, were switched to either secukinumab low dose or secukinumab high dose treatment group starting at Week 12 and for the remainder of the study according to their baseline randomization
  6. 6. • Extension treatment period (Week 52 until Week 236): At the end of the maintenance period, all patients on secukinumab entered the extension treatment period and continued to receive the same previous allocated dose of secukinumab. In the extension treatment period, between site visits, secukinumab was administered every 4 weeks at home, either by the patient (self-injection only for adolescents of at least 12 years of age and under supervision) or by the caregiver. In case a patient or caregiver did not feel confident in performing home administrations, the patient was allowed to receive administration at site • Follow-up period (16 weeks): Patients entered the treatment- free follow-up period of 16 weeks if they: discontinued treatment at any point; were placebo patients who completed Week 12 and were PASI 75 responders; were etanercept patients who completed Week 52; were secukinumab patients who completed the extension treatment period. This period’s duration was only 8 weeks for placebo PASI 75 responders. Exceptionally, patients who had to start other systemic therapies after stopping study treatment were permitted to terminate the treatment-free follow-up earlier
  7. 7. Inclusion criteria • Eligible patients were aged 6 to ≤18 years at the time of randomization— patients aged 12 to ≤18 years were enrolled from beginning of trial, and patients aged 6 to <12 years were enrolled after positive DMC recommendation following review of data from approximately first 80 adolescents • severe plaque psoriasis at randomization [PASI ≥ 20, Investigator’s Global Assessment modified 2011 (IGA mod 2011) score of 4 and body surface area (BSA) involvement of ≥10%], history of plaque psoriasis ≥3 months and patients regarded by the investigator to be candidates for systemic therapy Exclusion criteria • exclusion criteria were forms of active psoriasis other than plaque-type psoriasis • active ongoing inflammatory diseases other than psoriasis that might confound evaluation of benefit of secukinumab and/or etanercept
  8. 8. Study objectives • The primary objective of the study was to demonstrate the superiority of secukinumab (LD and HD) over placebo at Week 12 as measured by proportion of patients achieving PASI 75 and IGA mod 2011 0 or 1 response • Secondary objective was to demonstrate superiority of secukinumab (LD and HD) over placebo at Week 12 as measured by proportion of patients achieving PASI 90 • Other secondary objectives: to evaluate efficacy of secukinumab vs. placebo with respect to PASI 100 at Week 12, PASI 75/90/100 and IGA mod 2011 0/1 over time up to Week 52, changes in Children’s Dermatology Life Quality Index (CDLQI) and achievement of CDLQI 0/1 at Week 12 and over time up to Week 52.
  9. 9. Results • Patient disposition • In total, 187 patients were screened, 162 of whom completed the screening phase and were randomized to the four treatmentgroups: secukinumab LD (n = 40), secukinumab HD (n = 40), placebo (n = 41) and etanercept (n = 41) (Fig. 2). Overall, 156 (96.3%) patients completed the induction period, 151 (97.4%) of whom entered the maintenance period; 140 (90.3%) patients completed the maintenance period. • Demographics and baseline disease characteristics • The mean age of patients was 13.5 years, predominantly female (59.9%) and 77.2% were aged ≥12 years. • The mean weight of the overall population was 53.47 kg and was similar in all treatment groups; 92.6% of the patients weighed ≥25 kg. • The mean total BSA affected by plaque-type psoriasis was 40.0% and mean PASI score was 28 for overall patients • All patients had a PASI score of >20 and an IGA mod 2011 score of 4 (severe disease) except 2 patients in the secukinumab HD group, one with PASI score <20 and other with IGA mod 2011 score of 3 (moderate disease). • The mean time since diagnosis of psoriasis was 5.22 years
  10. 10. Efficacy • The study met the co-primary endpoints; both secukinumab doses (LD and HD) were superior (P < 0.0001) to placebo with respect to PASI 75 response (80.0% and 77.5% vs. 14.6%) and IGA mod 2011 0 or 1 response (70.0% and 60.0% vs. 4.9%) at Week 12 (Fig. 3). The study met the key secondary endpoint; both secukinumab doses (LD and HD) were superior (P < 0.0001) to placebo with respect to PASI 90 response (72.5% and 67.5% vs. 2.4%) at Week 12 At Week 12, PASI 100 response was achieved by 30.0% and 27.5% of patients in secukinumab LD and HD groups, respectively, and none of the patients in the placebo group • At Week 12, both secukinumab dose groups (LD and HD) achieved significantly higher (P < 0.05) response vs. etanercept with respect to IGA mod 2011 0/1 (70.0% and 60.0% vs. 34.1%) and PASI 90 (72.5% and 67.5% vs. 29.3%), respectively. • Both secukinumab dose groups (LD and HD) demonstrated efficacy as early as Week 4 (PASI 75/90/100: LD, 32.5%/12.5%/7.5% and HD, 55.0%/22.5%/7.5.% vs. etanercept, 12.2%/2.4%/0% and IGA 0 or 1: LD, 15.0% and HD, 32.5% vs. etanercept, 2.4%).
  11. 11. • Both secukinumab dose groups (LD and HD) continued to show higher PASI 75/90/100 and IGA mod 2011 0 or 1 responses compared to the etanercept group at each visit up to Week 52 • The responses in both groups (LD &HD)were higher compared to both the placebo and the etanercept groups throughout the induction period, and continued to be higher than the etanercept group up to Week 52. • The mean baseline PASI score was ~28 in all the treatment groups. At Week 12, the mean PASI scores were decreased (improved) from baseline by 82.9% in the secukinumab LD group (reaching 5.12) and by 79.9 % in the secukinumab HD group (reaching 5.56) compared to 29.3% in the placebo group (reaching 19.89) and 74.2 % in the etanercept group (reaching 7.50). At Week 52, the mean PASI scores decreased further from baseline by 92.6% in the secukinumab LD group (reaching 2.13) and by 91.8% in the secukinumab HD group (reaching 2.49), while the etanercept group showed a decrease in PASI score by 77.7% (reaching 7.24).
  12. 12. • Health-related quality of life • At Week 12, the proportion of patients achieving CDLQI score of 0 or 1 in both secukinumab dose groups (LD: 44.7% and HD: 50%) was significantly higher compared with the placebo group (15%) (P < 0.05 for both comparisons) and were numerically higher than the etanercept group (36.6%) . At Week 52,they were numerically higher (LD: 60.6% and HD: 66.7%) compared to etanercept (44.4%). • Safety • incidence of treatment-emergent AEs up to Week 52 was similar in the ‘any secukinumab LD’ group (80.4%), the ‘any secukinumab HD’ group (81%) and the etanercept group (82.9%) • The most commonly affected system organ class (SOC) was ‘Infections and infestations. • The higher incidence of AEs in this SOC was mainly driven by non-serious nasopharyngitis, pharyngitis, rhinitis and upper respiratory tract infections. • No deaths were reported up to the Week 52 data cut-off • During the 12-week induction period, 7 patients presented with injection site reactions
  13. 13. Discussion • Both secukinumab doses (LD and HD) were superior to placebo with respect to the co-primary endpoints of PASI 75 and IGA mod 2011 0 or 1 response and the key secondary endpoint of PASI 90 at Week 12 (P < 0.0001 for all comparisons • Secukinumab treatment demonstrated further improvement in the PASI 75/90/100 and IGA mod 2011 0/1 responses peaking around Week 24 and maintained up to Week 52 • Higher response rates were observed with secukinumab HD compared to LD in the bodyweight category ‘≥50 kg’. • Both secukinumab doses (LD and HD) demonstrated greater clinical improvement compared to etanercept throughout the study up to Week 52 • Results of the patient-reported outcome of CDLQI indicated continuous improvements in the • health-related quality of life and functional ability of the secukinumab-treated patients (to a larger extent in the HD group) compared to etanercept patients at Week 52 • Secukinumab was well tolerated at both doses (LD and HD). Conclusion • Both doses of secukinumab demonstrated high and sustained efficacy up to Week 52 in clearing skin and improving health-related quality of life with a favourable safety profile in paediatric patients with severe chronic plaque psoriasis.
  14. 14. Moderate-to-severe atopic dermatitis in adolescents treated with dupilumab: A multicentre Italian real- world experience • DOI: 10.1111/jdv.18141 • Received: 18 December 2021; revised: 12 February 2022; Accepted: 23 March 2022
  15. 15. Introduction • Atopic dermatitis (AD) is a complex disease with an interplay between abnormal immune response, genetic impairment of skin barrier and environmental factors. • Global AD prevalence is increasing in all ages: in children up to 20%,2 while in adults and elderly up to 10%. • Adolescent AD is frequently associated with difficulties in building social relationships and in maintaining good school performance, to bullying, depression and anxiety as well as suicidal ideation. • Dupilumab is an antiinterleukin-4-receptor-a monoclonal antibody blocking signalling of interleukins 4 and 13 and inhibiting the differentiation of naive T cells into T helper (Th) 2 cells.
  16. 16. • Herein, the author describe our Italian real-world experience to evaluate the clinical features of 139 AD patients aged from ≥12 to <18 years and the effectiveness and safety of dupilumab in a 16 week prospective observational study.
  17. 17. Materials and methods Methods Adolescents were enrolled in the study according to the following inclusion criteria 1. Age ≥ 12 years 2. Diagnosis of AD made by an expert, board-certified dermatologist; 3. Eczema Area and Severity Index (EASI) ≥24 or localization in visible or sensible areas (face, neck, hands or genitalia) 4. Numeric Rating Scale (NRS) itch ≥7 or Children Dermatology Life Quality Index (CDLQI) ≥10.
  18. 18. • Dupilumab was administered subcutaneously (SC) at label dosage: for adolescents <60 kg a loading dose of 400 mg (2 x 200 mg SC injections) followed by 200 mg (1 SC injection) Q2W; for adolescents ≥60 kg, a loading dose of 600 mg (2 x 300 mg SC injections) followed by 300 mg (1 SC injection) Q2W. • Patients with an observational period of at least 16 weeks were consecutively included in the study. • The following demographic and clinical data were recorded at baseline- 1. Age, gender, age of onset and clinical course (childhood or adolescent onset with persistent or relapsing course), 2. Clinical phenotype of AD 3. Comorbidities (atopic and non-atopic), 4. Concomitant medications or procedures and efficacy outcomes to previous treatments. • Disease severity was assessed at baseline and after 16 weeks of dupilumab therapy using EASI score (range 0–72), pruritus and sleep loss NRS score (range 0– 10) evaluated as peak score during the past 7 days and CDLQI score (range 0–30).
  19. 19. Results • A total of 139 AD adolescent patients [males 75 ; females 64 ]treated with dupilumab during the reference period were enrolled in the study. Demographics and baseline disease characteristics 1. the mean values of age, weight and BMI were 15.1 years, 60.2 Kg and 22.0 Kg/m2 , respectively. 2. Among atopic comorbidities, rhinitis was the most frequent (51.1%), followed by asthma (28.1%), conjunctivitis (25.9%) and food allergy (10.1%). 3. Clinical manifestations of AD occurred within the first year of life in 90 patients (64.7%) and after 1 year of life in 49 (35.3%). 4. Flexural eczema and head and neck eczema were the most frequent clinical phenotypes , followed by hand eczema, portrait-like dermatitis, diffuse eczema, eczema nummulare-like, prurigo nodularis-like and erythrodermia.
  20. 20. • Almost all AD adolescents received at least one systemic treatment for AD. • According to bodyweight, 65 adolescents received a loading dose of 400 mg followed by 200 mg Q2W and 74 a loading dose of 600 mg followed by 300 mg Q2W. • A significant improvement in EASI, NRS itch, NRS sleep loss and CDLQI was observed after 16 weeks of treatment with dupilumab • The mean EASI score at baseline was 26.2 +/- 7.7 and significantly reduced to 5.3 +/- 4.5 at 16 weeks (P < 0.01), with a mean percentage reduction of 79.8%. • The mean percentage reduction in CDLQI score from baseline (14.4 +/- 6.4) to 16 weeks (3.9 +/- 3.4) was 72.9% (P < 0.01). • NRS sleep loss had a mean value of 6.6 +/- 2.9 at baseline vs. 1.6 +/- 2.1 at 16 weeks (P < 0.01; mean percentage reduction of 75.8%). • The mean NRS itch showed a significant reduction from baseline to timepoint (8.2 +/- 1.5 at baseline vs. 2.9 +/- 2.3 at week 16; P < 0.01; mean percentage reduction of 64.6%).
  21. 21. • Overall, almost all patients (99.3%) reached EASI-50, while EASI-75 and EASI-90 were reached by 64.5% and 33.3% of adolescents, respectively; complete clear skin was achieved by 15.9% of adolescents. • According to gender, dupilumab effectiveness resulted higher in females than in males for EASI75, EASI-90 and EASI-100, reaching statistical significance for EASI-75 (P < 0.05). • Twenty-eight out of 139 (20.1%) adolescents experienced at least one adverse event (AE) during the 16-week treatment. • Fifteen (10.8%) were diagnosed with mild-to-moderate conjunctivitis. Other AEs were flushing , injection-site reaction , fatigue, diarrhoea, headache and herpes simplex . None of the patients discontinued dupilumab due to AEs.
  22. 22. Discussion • AD in adolescents, unlike childhood and adult AD, has been rarely approached from clinical and therapeutic perspectives .Therefore, quality of life (QoL) is significantly reduced in adolescents with AD and also in their caregivers, who often experience low sleep quality and deteriorated psycho-emotional state. • Dupilumab is currently the only innovative systemic therapy for moderate-to- severe AD in adolescents. • In this 16-week prospective observational study conducted in 30 Italian Dermatologic Clinics, the author evaluated the effectiveness and safety of dupilumab in a large study group of adolescents who started dupilumab immediately after its reimbursement.
  23. 23. • Patients, with a long-standing AD (mean duration 13.0 years), were mostly normal weight (115/139, 82.7%), while 14 (12.3%) were overweight and obese. • Atopic comorbidities were present in 85/139 adolescents (61.2%) confirming the high prevalence of other atopic diseases in this setting of AD patients. • Regarding AD clinical features, we documented coexistence of more than 1 phenotype in most of the adolescents (126/139, 88.5%), with flexural, head and neck, and hand eczema the most 3 frequent confirming that adolescent AD is a bridge between childhood and adult AD. • Almost all patients (136/139, 97.8%) were previously treated with at least one systemic drug . At baseline, 39 patients were in treatment with Cs (22) and CyA (17) with unsatisfactory results. These systemic drugs were gradually tapered and stopped within 4 weeks in all patients.
  24. 24. • In this multicentre real-life experience on dupilumab in adolescents with moderate-to-severe AD, the effectiveness of dupilumab at Week 16 was excellent. • EASI change from baseline (79.8%) was significantly higher than that observed in LIBERTY AD ADOL14 (65.9%) and similar to that observed in LIBERTY AD PED- OLE15 (81.6%). • Regarding NRS itch and NRS sleep loss scores, an improvement greater than that observed in clinical trials was documented. • Regarding QoL, the study documented a reduction (10.5 points) in CDLQI higher than that in LIBERTY AD ADOL14 (8.5 points). • In terms of improvement from baseline EASI ,EASI-50 was reached by almost all of the patients (99.3%), EASI-50 was reached by almost all of patients (99.3%), EASI- 90 was achieved by 33.3% of patients.
  25. 25. • EASI improvement according to gender and clinical baseline characteristics, the study documented a better therapeutic outcome in females than in males. • The data suggest that low BMI, low EASI, normal serum total IgE and early age of onset may positively influence the effectiveness of dupilumab in terms of EASI-75, EASI-90 and EASI-100. • All phenotypes showed similar response to dupilumab therapy, except for diffuse eczema in which dupilumab resulted more effective in terms of EASI-90 and EASI100 compared with hand eczema and eczema nummulare-like. • Effectiveness of dupilumab was also confirmed by the reduction in topical therapies, especially for Cs stopped in 54.1% of our patients and by the discontinuation in all patients of systemic Cs and CyA within 3 and 4 weeks , respectively. • The tolerability of dupilumab during the study period, reporting AEs in 20.1%, consistently less than that observed in clinical trials (72.0%14 and 60.0%15), and none of patients discontinued dupilumab due to Aes.
  26. 26. Conclusion • In conclusion, the strength of this real-world study is the large number of AD adolescents treated with dupilumab, not selected as in clinical trials. Limitations of this study include that part of patients (28.1%) had concomitant systemic therapy during the first 3–4 weeks that could influence baseline disease severity, effectiveness and safety of dupilumab. • Dupilumab in adolescent AD showed excellent effectiveness at week 16 with consistent improvement of all clinical scores.