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

Discussion

IXE was superior to placebo for both coprimary endpoints and all gated secondary endpoints. Significant improvements in skin and itch were observed as early as week 1 and persisted through week 48. Itch affects many paediatric patients with psoriasis and has a high impact on quality of life.[8,9] In IXORA-PEDS, nearly 75% of patients reported Itch NRS ≥ 4 at baseline. IXE provided clinically meaningful improvements in itch for nearly 80% of patients by week 48. IXE also provided significant improvements over placebo at week 12 in health-related quality of life and clearance of scalp and genital psoriasis. Responses with IXE were generally consistent across weight subgroups, although analysis in patients with baseline weight < 25 kg was limited by the small sample size.

Most AEs were mild to moderate in severity, SAEs occurred in < 7% of patients, < 2% of patients discontinued due to AEs, and no deaths occurred. Serious infections were reported in approximately 1% of patients, but there were no discontinuations due to infection-related TEAEs. Crohn's disease was reported in one patient during the double-blind treatment period and in three patients during the maintenance period, each adjudicated as probable Crohn's disease.

PASI 75 was achieved by 89% of patients receiving IXE Q4W at week 12, a result consistent with the phase III UNCOVER-1 (89%), UNCOVER-2 (90%) and UNCOVER-3 studies (87%) in adult patients with moderate-to-severe psoriasis.[10,11] PASI 75 responses persisted through week 48 (90%), which was greater than week 60 responses in UNCOVER-3 (83%).[10] More patients achieved complete skin clearance (PASI 100) with IXE at week 12 in IXORA-PEDS (50%) than in UNCOVER-3 (38%), but responses were similar between IXORA-PEDS (55%) at week 48 and UNCOVER-3 (55%) at week 60. Placebo responses in IXORA-PEDS were greater than those observed in adults in the UNCOVER studies. At week 12, PASI 75 was achieved by 25% of paediatric patients receiving placebo in IXORA-PEDS, compared with 3·9% (UNCOVER-1), 2·4% (UNCOVER-2) and 7·3% (UNCOVER-3) in adult patients.[10,11] These findings are consistent with conclusions from reviews and meta-analyses of clinical trials, in which placebo response rates in paediatric populations are generally higher than in adult populations.[12] The placebo effect observed in IXORA-PEDS was considerably lower for more stringent endpoints such as PASI 90 (5%) and PASI 100 (2%) at week 12, which was similar to placebo responses observed in adults (PASI 90: UNCOVER-1, 0·5%; UNCOVER-2, 0·6%; UNCOVER-3, 3·1%; PASI 100: UNCOVER-1, 0%; UNCOVER-2, 0·6%; UNCOVER-3, 0%).[10,11]

IXE was recently approved by the FDA for moderate-to-severe psoriasis in patients aged ≥ 6 years and is the first biologic therapy approved for paediatric psoriasis that targets IL-17A. Other biologic therapies approved for paediatric psoriasis include two tumour necrosis factor inhibitors (etanercept and adalimumab) and the IL-12/23 antagonist, ustekinumab. PASI 75 was achieved by 57% (week 12) and 58% of patients (week 16) in phase III studies of etanercept (0·8 mg kg−1) and adalimumab (0·8 mg kg−1) for paediatric psoriasis, respectively.[13,14] In adolescent patients (aged 12–17 years) with moderate-to-severe psoriasis, PASI 75 response at week 12 was achieved by 81% of patients receiving ustekinumab.[15]

Approved use of these treatments differs across geographies, ages and severities. The FDA approved etanercept and ustekinumab in patients ≥ 4 and ≥ 12 years old, respectively, for moderate-to-severe plaque psoriasis but has not approved adalimumab for paediatric psoriasis. The European Medicines Agency approved etanercept and adalimumab in patients with severe psoriasis who are ≥ 6 and ≥ 4 years old, respectively, and ustekinumab for moderate-to-severe psoriasis in patients ≥ 6 years old. This study suggests that IXE may be an additional and efficacious treatment option for paediatric patients with moderate-to-severe plaque psoriasis.

A strength of IXORA-PEDS is enrolment of a geographically diverse population. IXE was administered on site during study visits to ensure consistent dosing and administration in paediatric patients. IXE provided consistent efficacy across weight subgroups; however, analysis of patients with baseline weight < 25 kg was limited to a small sample size of three patients. IXE Q4W showed significantly greater skin improvements [PASI 90, PASI 100 and sPGA (0)] compared with etanercept, although this comparison was for patients with severe psoriasis in etanercept-approved countries outside the USA. Limitations of this comparison include a small patient number and the comparison of double-blind IXE Q4W vs. open-label etanercept. However, the outcomes assessors were blinded to treatment assignments to minimize potential bias.

In conclusion, IXE provided rapid, statistically significant and clinically meaningful improvements over placebo in skin, itch and health-related quality of life that persisted for up to 48 weeks in paediatric patients with moderate-to-severe plaque psoriasis. The safety profile of IXE was generally consistent with that in adults with moderate-to-severe plaque psoriasis. Thus, IXE may be an additional therapeutic option for moderate-to-severe paediatric psoriasis.

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