Efficacy and Safety of Ixekizumab in a Phase III, Randomized, Double-Blind, Placebo-Controlled Study in Paediatric Patients With Moderate-to-Severe Plaque Psoriasis (IXORA-PEDS)

A.S. Paller; M.M.B. Seyger; G. Alejandro Magariños; J. Bagel; A. Pinter; J. Cather; S. Keller; C. Rodriguez Capriles; R. Gontijo Lima; G. Gallo; C.A. Little; E. Edson-Heredia; L. Li; W. Xu; K. Papp

Disclosures

The British Journal of Dermatology. 2020;183(2):231-241. 

In This Article

Results

Of 199 patients screened, 171 (86%) were randomized to placebo (n = 56) or IXE Q4W (n = 115); 53 (95%) and 113 (98%), respectively, completed the double-blind treatment period (Figure 1). Overall, 166 patients entered the maintenance period and 89% (152 of 171) completed week 48. Three (placebo) and two (IXE Q4W) patients discontinued during the double-blind treatment period and 14 discontinued during the maintenance period. Figure S1 (see Supporting Information) presents a flow diagram for patients with severe psoriasis in etanercept-approved countries.

Figure 1.

Patient flow diagram through Week 48 of IXORA-PEDS. Q4W, every 4 weeks.

The baseline demographics and disease characteristics were similar between treatment arms (Table 1; and Table S3; see Supporting Information). The mean ± SD age was 13·5 ± 3·04 years (range 6–17), 58% (n = 99) of patients were female, and most (84%, n = 140) were of white race. Most patients (73%, n = 125) weighed > 50 kg, 25% (n = 43) weighed ≥ 25 and ≤ 50 kg, and 2% (n = 3) weighed < 25 kg. The mean ± SD duration of psoriasis symptoms was 4·7 ± 3·17 years and the mean ± SD PASI score was 19·7 ± 7·65. Baseline nail (NAPSI > 0), scalp (PSSI > 0), palmoplantar (PPASI > 0) and genital psoriasis were present for 27% (n = 46), 89% (n = 152), 15% (n = 26) and 32% (n = 55) of patients, respectively. Most patients (72%, n = 123) had baseline Itch NRS ≥ 4 and all patients (n = 171) had baseline PatGA > 0. The mean ± SD DLQI and CLDQI scores were 9·4 ± 4·92 and 8·1 ± 5·30, respectively.

The coprimary and all gated secondary objectives were achieved. IXE was superior to placebo for both coprimary endpoints of PASI 75 (IXE Q4W: 89%, placebo: 25%, P < 0·001) and sPGA (0,1) (IXE Q4W: 81%, placebo: 11%, P < 0·001) at week 12 (Figure 2 and Table 2). IXE was superior to placebo at week 12 for the gated secondary endpoints of PASI 90 (IXE Q4W: 78%, placebo: 5%, P < 0·001), sPGA (0) (IXE Q4W: 52%, placebo: 2%, P < 0·001), PASI 100 (IXE Q4W: 50%, placebo: 2%, P < 0·001) and Itch NRS ≥ 4 (IXE Q4W: 71%, placebo: 20%, P < 0·001) (Figure 3 and Table 2); and at week 4 for PASI 75 (IXE Q4W: 54%, placebo: 9%, P < 0·001) and sPGA (0,1) (IXE Q4W: 48%, placebo: 7%, P < 0·001) (Figure 2).

Figure 2.

Proportions of patients achieving (a) ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) and (b) static Physician's Global Assessment score of 0 or 1 [sPGA (0,1)] for up to 48 weeks of treatment with ixekizumab (nonresponder imputation). Ixekizumab vs. placebo P-values during the 12-week double-blind treatment period are indicated as *P < 0·05, ‡P < 0·001. Error bars indicate 95% confidence intervals. Analyses of PASI 75 and sPGA (0,1) at week 12 (coprimary endpoints) and at week 4 (gated secondary endpoints) were included in the gated multiple testing strategy. Analyses at other timepoints were not adjusted for multiplicity.

Figure 3.

Proportions of patients achieving (a) ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90); (b) static Physician's Global Assessment score of 0 [sPGA (0)]; (c) PASI 100 and (d) ≥ 4-point improvement from baseline in itch numerical rating scale (Itch NRS) for up to 48 weeks of treatment with ixekizumab (nonresponder imputation). Ixekizumab vs. placebo P-values during the 12-week double-blind treatment period are indicated as †P < 0·01, ‡P < 0·001. Error bars indicate 95% confidence intervals. Analyses of PASI 90, sPGA (0), PASI 100 and Itch NRS ≥ 4 at week 12 (gated secondary endpoints) were included in the gated multiple testing strategy. Analyses at other timepoints were not adjusted for multiplicity.

Significantly (P < 0·001) more patients achieved PASI 50 at week 12 with IXE Q4W (92%) than with placebo (38%) (Table 2), with significant differences as early as week 1 (IXE Q4W: 36%, placebo: 7%, P < 0·001). IXE provided significant improvements over placebo as early as week 1 for PASI 75 (P = 0·032) and Itch NRS ≥ 4 (P = 0·008), and as early as week 4 (P < 0·001) for PASI 90, PASI 100, sPGA (0,1) and sPGA (0) (Figures 2 and 3). In patients with severe psoriasis in etanercept-approved countries, IXE resulted in significantly greater response than etanercept for PASI 90 (IXE Q4W: 76%, etanercept: 40%, P = 0·003), PASI 100 (IXE Q4W: 61%, etanercept: 53%, P < 0·001) and sPGA 0 (IXE Q4W: 63%, etanercept: 17%, P < 0·001). Responses with IXE Q4W were numerically greater than with etanercept for PASI 75 (IXE Q4W: 84%, etanercept: 63%, P = 0·089) and sPGA (0,1) (IXE Q4W: 76%, etanercept: 53%, P = 0·070), but were not statistically significant (Table 3; and Figure S2; see Supporting Information).

CDLQI/DLQI (0,1) and PatGA (0,1) responses at week 12 were significantly (P < 0·001) greater with IXE than with placebo (Table 2). At week 12, significantly more patients with IXE than with placebo achieved clearance of baseline scalp (PSSI = 0, P < 0·001) and genital psoriasis (P < 0·001). IXE Q4W resulted in a significantly greater mean change from baseline than placebo at week 12 for Itch NRS (P < 0·001), NAPSI (P = 0·005), PSSI (P < 0·001) and PPASI (P = 0·006).

Responses at week 12 were sustained or further improved through week 48 (Figures 2 and 3 and Table 2). For patients initially randomized to IXE Q4W, responses at week 48 were 92% (PASI 50), 90% (PASI 75), 83% (PASI 90), 55% (PASI 100), 81% [sPGA (0,1)], 57% [sPGA (0)] and 78% (Itch NRS ≥ 4). Sustained or additional improvements through week 48 were observed for CDLQI/DLQI (0,1), PatGA (0,1) and clearance of nail, scalp, palmoplantar or genital psoriasis.

In analyses by baseline weight, IXE resulted in significantly greater responses than placebo at week 12 for PASI 75, PASI 90, PASI 100, sPGA (0,1) and sPGA (0) in the subgroups of ≥ 25 kg to ≤ 50 kg and > 50 kg, and responses with IXE Q4W were numerically similar between these two subgroups (Table S4; see Supporting Information). Statistical comparisons of responses in patients with baseline weight < 25 kg were limited due to the small number of patients in this category (placebo: n = 1, IXE Q4W: n = 2). Both patients receiving IXE Q4W achieved PASI 75 and one (50%) achieved PASI 90, PASI 100, sPGA (0,1) and sPGA (0) at week 12; the patient receiving placebo achieved none of these endpoints.

During the double-blind treatment period, TEAEs were reported in 64 (56%) and 25 (45%) patients receiving IXE Q4W and placebo, respectively; no TEAEs were severe (Table 4). One (1%) SAE (IXE Q4W) was reported and one (2%) patient (placebo) discontinued due to an AE. In the all-IXE safety population, TEAEs occurred in 161 (82%) patients; nine (5%) were severe. Thirteen patients (7%) reported SAEs (Table S5; see Supporting Information) and three (2%) discontinued due to an AE (two with Crohn's disease and one with pityriasis rubra pilaris). In the etanercept arm, 13 patients (43%) reported TEAEs (two severe, 7%), one (3%) SAE was reported, and there were no discontinuations due to AEs (Table S6; see Supporting Information). No deaths were reported.

During the double-blind treatment period, treatment-emergent infections were reported in 37 (32%) patients receiving IXE Q4W and 14 (25%) receiving placebo; no serious infections were reported. In the all-IXE safety population, 129 (66%) patients reported treatment-emergent infections; one (1%) was severe (pharyngitis). Two (1%) patients reported serious infections (one acute otitis media and one tonsillitis) and no opportunistic infections were reported. In the etanercept arm, six (20%) infection-related TEAEs were reported and there were no serious infections.

During the double-blind treatment period, 14 (12%) patients receiving IXE Q4W and one (2%) receiving placebo reported injection-site reactions. In the all-IXE safety population, 39 (20%) patients reported injection-site reactions. There were no injection-site-related SAEs, and one severe injection-site reaction (injection-site pain) was reported. Safety related to depression, allergic reaction or hypersensitivity, cytopenia, and hepatic events is summarized in Table 4; none of which were SAEs. There were no TEAEs of grade 3 or 4 cytopenia reported and there were no reports of anaphylaxis, malignancies, or interstitial lung disease.

One patient receiving IXE Q4W reported an AE of diarrhoea during the double-blind treatment period. This patient also reported intestinal inflammatory disease and abdominal pain at study day 1. The patient discontinued due to the AE of intestinal inflammatory disease and the case was adjudicated as probable Crohn's disease. Three patients reported TEAEs of IBD (adjudicated as probable Crohn's disease) during the maintenance period, each of whom reported SAEs and discontinued from the study. These discontinuations were due to withdrawal by patient (n = 1), AE of Crohn's disease (n = 1) and physician decision because of suspected IBD (n = 1). One of these patients reported autoimmune comorbidities of atopic dermatitis, alopecia areata and psoriatic arthritis. Appendix S8 (see Supporting Information) provides additional details regarding safety.

Of 194 evaluable patients, 53 (27%) were TE-ADA positive; 29 (15%) were low titre, 22 (11%) were moderate titre and two (1%) were high titre. Neutralizing antidrug antibodies were detected in five (3%) evaluable patients. The presence of TE-ADAs had no impact on efficacy regardless of neutralizing antibody status, and there were no consistent temporal relationships between the presence of TE-ADAs and the occurrence of injection-site reactions or allergic reaction or hypersensitivity TEAEs.

processing....