3.1 Patient Disposition

Of the 84 randomized patients (secukinumab LD [N = 42] and secukinumab HD [N = 42]), 79.8% (67 of 84) completed the treatment (secukinumab LD [N = 31] and secukinumab HD [N = 36]), whereas 20.2% (17 of 84) discontinued it (secukinumab LD [N = 11] and secukinumab HD [N = 6]). The most common reason for discontinuation during the entire study treatment was lack of efficacy (5 [11.9%]) and patient decision (2 [4.8%]) in the secukinumab LD group and AE (2 [4.8%]) and pregnancy (2 [4.8%]) in the secukinumab HD group (Fig. 1).

Fig. 13.2 Demographics and Baseline Disease Characteristics

The demographics and baseline disease characteristics were comparable between the secukinumab LD and HD groups and have been reported previously [14]. The mean age of the patients was 12.6 years and was similar in both treatment groups. Most patients (51 of 84 patients; 60.7%) belonged to the age group of 12 to < 18 years (Supplementary Table 1).

3.3 Efficacy

PASI 75/90/100 and IGA 0/1 responses remained high in both treatment groups from week 12 through EOT (week 208). At week 208, secukinumab-treated patients showed sustained PASI 75/90/100 (secukinumab LD: 96.3%/88.9%/51.9%; secukinumab HD: 87.9%/81.8%/72.7%) and IGA mod 2011 0/1 (secukinumab LD: 85.2%; secukinumab HD: 84.8%) responses (Fig. 2a–d). PASI 75 and IGA mod 2011 0/1 response rates increased continuously from baseline, reaching maximum values between weeks 24 and 32; thereafter, the PASI 75 and IGA mod 2011 0/1 response rates remained similar between the LD and HD groups at almost all timepoints until week 208 (Fig. 2a and b). In most assessments, PASI 90 responses were slightly higher in the HD group after week 24 until week 156 but lower after week 156 and until week 208 (Fig. 2c). After week 24 through week 208, PASI 100 response was numerically greater in the HD group (Fig. 2d).

Fig. 2

Efficacy response rates up to week 208 using observed cases a IGA mod 2011 0/1; b PASI 75; c PASI 90; d PASI 100. HD high dose, IGA mod 2011 Investigator’s Global Assessment modified 2011, LD low dose, PASI Psoriasis Area and Severity Index

At week 12, mean percentage change in PASI score from baseline was − 92.6% (mean absolute score: 1.42) in the LD group and − 93.9% (mean absolute score: 1.19) in the HD group. The mean PASI score remained low in both treatment groups, from week 12 through week 208, and at week 208, mean percentage change in PASI scores from baseline was − 95.7% (mean absolute score: 0.76) with secukinumab LD and − 94.5% (mean absolute score: 1.07) with secukinumab HD (Fig. 3 and Supplementary Fig. 1).

Fig. 3

Change in PASI scores from baseline by visit (observed cases) over time up to week 208. HD high dose, LD low dose, PASI Psoriasis Area and Severity Index

3.4 Health-Related Quality of Life

CDLQI 0/1 response remained high in both treatment groups from week 12 through week 208 (secukinumab LD: 75.0%; secukinumab HD: 88.2%; Fig. 4). CDLQI 0/1 response rates were higher in the HD group after week 180 to 208 compared with the LD group. Mean percentage change in CDLQI total score was overall comparable between the two treatment groups up to week 52. At week 52, mean absolute change in CDLQI total score was − 9.2 (− 84.9% from baseline) and − 12.8 (− 89.6% from baseline) in the LD and HD groups, respectively, and between weeks 52 and 208, the mean absolute and percent change in CDLQI total score was generally similar in both groups. At week 208, the mean absolute percent change from baseline in CDLQI total score was − 9.3 (− 92.3%) and − 11.2 (− 92.7%) in the LD and HD groups, respectively (Supplementary Fig. 2).

Fig. 4

CDLQI 0/1 response up to week 208 in LOCF analysis. N represents the number of patients in each treatment group included in the full analysis set. CDLQI Children’s Dermatology Life Quality Index, HD high dose, LD low dose, LOCF last observation carried forward

3.5 Relapse and Rebound

The proportion of patients experiencing at least one relapse during the entire treatment period was higher in the secukinumab LD group. After the last study treatment, 8 of 41 (19.5%) patients in the LD group and 4 of 41 (9.8%) patients in the HD group had relapse. Of the eight patients who experienced relapse in the LD group, three had discontinued the treatment owing to lack of efficacy. The remaining five patients had their relapse between 120 and 157 days after their last dose. Similarly, the four patients in the HD group had their first relapse event 98–140 days after their last dose. No patient experienced rebound or rebound-like events up to 8 and 12 weeks, respectively, after the last study treatment.

3.6 Safety

The median duration of exposure during the entire treatment period was 1513.0 days in the secukinumab LD group and 1512.5 days in the secukinumab HD group. Cumulative exposure across the secukinumab treatment groups was similar, totaling 313.9 patient-years (PYs) in the “any secukinumab” group. Overall, 81.0% (68 of 84) of patients had at least one AE. The incidence of AEs was comparable between the secukinumab LD (33 of 42 [78.6%]) and HD (35 of 42 [83.3%]) groups (Table 1). No deaths were reported during the entire treatment period. AEs leading to treatment discontinuation for the entire treatment period were also infrequent and comparable in both treatment groups (one patient in the LD group and two patients in the HD group). Nonfatal SAEs during the entire treatment period were reported in four (9.5%) patients in the LD group and two (4.8%) patients in the HD group. Consistent with the week 52 results, the most frequently affected SOCs in the “any secukinumab” group were infections and infestations (55 of 84, 65.5%), gastrointestinal disorders (19 of 84, 22.6%), and skin and subcutaneous tissue disorders (19 of 84, 22.6%).

Table 1 Overall safety profile—entire treatment period (safety analysis set)

The exposure-adjusted incidence rates (EAIR) of the most commonly reported SOCs were similar in the secukinumab LD and HD groups under infections and infestations (secukinumab LD, 35.0/100 PYs; secukinumab HD, 41.9/100 PYs). The EAIR of AEs under the SOC skin and subcutaneous tissue disorders was numerically higher in the secukinumab LD group (9.5/100 PYs) than in the HD group (4.8/100 PYs).

The most commonly reported AEs by PT were coronavirus disease 2019 (COVID-19); (secukinumab LD [12 of 42  and EAIR 8.9/100 PYs] and HD [9 of 42  and EAIR 6.2/100 PYs]), nasopharyngitis (secukinumab LD [13 of 42 and EAIR 10.7/100 PYs] and HD [7 of 42 and EAIR 5.2/100 PYs]), and acne (secukinumab LD [7 of 42  and EAIR 5.0/100 PY] and HD [2 of 42  and EAIR 1.3/100 PY]).

The most frequently reported AEs were under the safety topic of infections and infestations (EAIRs: “any secukinumab” LD, 35.0/100 PYs; “any secukinumab” HD, 45.4/100 PYs). Candida infections (high-level term [HLT]) were reported in two patients in the LD group (EAIR: 1.3/100 PYs [skin candida, 1; esophageal candidiasis, 1]) and none in the HD group. The proportion of patients with AEs in the safety topic of hypersensitivity (standardized MedDRA Query [SMQ], narrow) in the “any secukinumab” LD group was 16.7% (n = 7; EAIR: 4.9/100 PYs) and that in the “any secukinumab” HD group was 2.4% (n = 1; EAIR: 0.6/100 PYs). The higher incidence of hypersensitivity in the LD group (SMQ, narrow) was mainly driven by PTs of angioedema, contact dermatitis, drug hypersensitivity, eczema, erythema nodosum, hand dermatitis, and penile dermatitis. Neutropenia and leukopenia PTs qualified under neutropenia (Novartis-customized MedDRA Query [NMQ], narrow, NMQ corresponds to groupings defined by MedDRA and additional custom groupings created by Novartis) and were reported in six patients (7.1%; 4 [EAIR, 2.8/100 PYs] from the LD group and 2 [EAIR, 1.3/100 PYs] from the HD group). Inflammatory bowel disease (IBD) (NMQ) occurred in one patient (EAIR, 0.6/100 PYs) each in the secukinumab LD and HD groups. Two patients discontinued treatment due to AE: one patient (LD group) owing to moderate SAE of Crohn’s disease and one patient (HD group) owing to a mild AE of hemorrhagic diarrhea (not diagnosed as IBD) both events were resolved with concomitant treatment (Crohn’s disease SAE was resolved with sequelae). Suicide/self-injury (SMQ) was reported in one patient in the secukinumab LD group (EAIR: 0.6/100 PYs). Details of the patient have been published previously [13]. Two pregnancies were reported in the HD group, which led to discontinuation of the study drug as required by the protocol. Both women gave birth to healthy babies.

3.7 Tanner Staging of Pubertal Development

Most patients at baseline were pubertal or postpubertal (Tanner stage score of ≥ 2). Tanner staging scores increased over time, and the patients consistently moved toward higher Tanner stage scores from baseline through the study course. At baseline, Tanner stage 4 or 5 was observed in 31.8% of male and 50.0% of female patients in the “any secukinumab” LD group, and in 52.9% of male and 60.0% of female patients in the “any secukinumab” HD group. By week 104, the proportion of patients with Tanner stage 4 or 5 increased to 57.1% in males and 66.7% in females in the “any secukinumab” LD group, and to 76.5% in males and 76.2% in females in the HD group. At week 208, most of the evaluable male and female patients in the secukinumab LD group (male, 66.7%; female, 75.0% versus male, 70.6%; female, 71.4% in the secukinumab HD group) reached Tanner stage 5 (full sexual maturation). In addition, no adverse events associated with retardation of sexual maturation were reported. These data indicate that both secukinumab LD and HD did not have any effect on the sexual maturation of the patients treated in the study (Supplementary Fig. 3).

3.8 Immunogenicity

ADA development with secukinumab treatment for 208 weeks was low; 7 patients (3 in the LD and 4 in the HD group; 7 of 84, 8.3%) presented with positive treatment-emergent ADAs, with 6 having positive ADAs only during treatment-free follow-up. None of these patients developed neutralizing antibodies.