Safety of Tildrakizumab for Moderate-to-Severe Plaque Psoriasis

Pooled Analysis of Three Randomized Controlled Trials

A. Blauvelt; K. Reich; K.A. Papp; A.B. Kimball; M. Gooderham; S.K. Tyring; R. Sinclair; D. Thaçi; Q. Li; N. Cichanowitz; S. Green; C. La Rosa


The British Journal of Dermatology. 2018;179(3):615-622. 

In This Article

Abstract and Introduction


Background: Short-term interleukin-23p19 inhibition by tildrakizumab improves plaque psoriasis and appears to be well tolerated.

Objectives: Safety and tolerability were assessed for up to 64 weeks of tildrakizumab therapy using pooled data from three randomized controlled trials for moderate-to-severe psoriasis.

Methods: Data pools for the placebo-controlled (up to 16 weeks) and full trial periods (up to 64 weeks) were analysed (n = 2081).

Results: In the placebo-controlled period, frequencies of treatment-emergent adverse events (TEAEs; range 47·9–54·0%), serious TEAEs (range 1·4–2·3%), discontinuations due to AEs (range 0·6–1·9%), major adverse cardiovascular events (MACEs; range 0·0–0·1%) and severe infections (range 0·0–0·3%) were comparable between tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept. In the full trial period, exposure-adjusted rates (patients per 100 patient-years) for TEAEs, serious TEAEs and discontinuations due to AEs with tildrakizumab 100 mg and 200 mg were lower than or comparable with the placebo rates, and lower than with etanercept. Exposure-adjusted rates of MACEs (range 0·0–0·5) and severe infections (range 0·9–2·0) were comparable among groups. No TEAEs of inflammatory bowel disease or suicide were reported. Candida skin infections were infrequent at frequencies of 0·1%, 0·3%, 0·0% and 0·0% for the tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and etanercept groups, respectively, in the placebo-controlled period, and exposure-adjusted rates of 0·2, 0·7, 0·0 and 0·0, respectively, in the full trial period. Oral candidiasis was also infrequent.

Conclusions: Up to 64 weeks of tildrakizumab was well tolerated, with low rates of serious TEAEs, discontinuations due to AEs, and AEs of clinical interest.


Targeting of cytokines involved in psoriasis pathogenesis has been a focus of therapy. Initially, tumour necrosis factor-α blockers became a successful treatment option, although these medications can be associated with infections and other side-effects.[1–3] The importance of the interleukin (IL)-23–T helper (Th)17 pathway in psoriasis has fuelled the development of IL-23 inhibitors.[4–9] IL-23 is elevated in psoriasis lesions,[10] and downregulation of IL-23 mRNA expression in lesions is associated with successful clinical responses to treatment.[11,12] Furthermore, IL-23 drives activation of human Th17 cells, which subsequently promote chronic inflammation and produce cytokines with downstream effects characteristic of psoriasis, such as keratinocyte activation and hyperproliferation.[13,14]

Tildrakizumab is a high-affinity, humanized, IgG1κ monoclonal antibody directed against the p19 subunit of IL-23. One phase II and two large phase III randomized controlled trials (RCTs) of tildrakizumab have been conducted in patients with moderate-to-severe chronic plaque psoriasis.[6,9] Tildrakizumab appeared to be well tolerated in all three trials, with low frequencies of serious adverse events (AEs) and discontinuations due to AEs.

Dose-associated risk of Candida albicans infections and inflammatory bowel disease has been reported with IL-17 blockers,[15–17] but not with the IL-23 inhibitors guselkumab or tildrakizumab.[4,6] This suggests that IL-23-independent IL-17A production may be preserved during anti-IL-23 therapy and thus protect against development of these specific side-effects. The present analysis further assessed the safety and tolerability of tildrakizumab for up to 64 weeks of use in a large group of patients using pooled data from the three previously reported RCTs.[6,9] In addition to candidiasis and inflammatory bowel disease, other important safety outcomes such as major adverse cardiovascular events (MACEs) and malignancy, which are possibly increased in patients with psoriasis vs. the general population, were assessed.[18–21]