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


This pooled analysis of three RCTs demonstrates that up to 64 weeks of tildrakizumab is well tolerated in a large group of patients with moderate-to-severe psoriasis. Frequencies and exposure-adjusted rates of TEAEs, treatment-related AEs, serious AEs and discontinuations due to AEs with tildrakizumab treatment were lower than or comparable with placebo rates.

Frequencies and exposure-adjusted rates of MACEs with tildrakizumab treatment were low and comparable with placebo, indicating no increased risk of MACEs. Analysis of MACEs in the pooled analysis was selected as a prespecified AE of interest because patients with psoriasis are at increased risk for cardiovascular events,[18–20] and initial reports during the development of briakinumab, an IL-12/23 inhibitor, suggested an imbalance of MACEs between briakinumab and placebo.[24] The concerns regarding increased MACEs contributed to the withdrawal of the briakinumab application from the U.S. Food and Drug Administration.[25] However, a combined analysis of trials of the IL-12/23 inhibitor ustekinumab did not reveal an increased risk of MACEs compared with the general population or in patients with psoriasis.[26]

Pooled analysis of 10 trials of secukinumab, an IL-17A inhibitor, also did not find an increased risk of MACEs.[17] Furthermore, a systematic review and meta-analysis of 38 RCTs found no indication of increased MACE risk vs. placebo with the licensed dose of any biologic for the treatment of moderate-to-severe psoriasis, including biologics that inhibit IL-23 or IL-17 (e.g. ustekinumab, secukinumab and ixekizumab).[27] To date, no pooled analyses investigating the risk of MACEs with the IL-23 inhibitor guselkumab have been published.

Patients with psoriasis appear to have an increased risk of malignancies, including nonmelanoma skin cancer.[21] In the current pooled analysis, frequencies and exposure-adjusted rates of malignancies, nonmelanoma skin cancer and melanoma skin cancer with tildrakizumab treatment were similar to those with placebo, indicating no increased risk of these events with tildrakizumab. There were two cases of pancreatic cancer in patients treated with tildrakizumab 200 mg.

The risk of infection is always a concern when a treatment inhibits a molecule in the immune system pathway. The infection frequency with tildrakizumab treatment during the placebo-controlled period was comparable with placebo, and exposure-adjusted rates during the full trial period were lower with tildrakizumab treatment than with placebo.

Worsening of inflammatory bowel disease[15] and increased frequency of Candida infections[16,17] have been noted during treatment with IL-17 inhibitors. In the current analysis, no new or worsening events of inflammatory bowel disease or suicide were associated with tildrakizumab treatment. The frequency and exposure-adjusted rates of Candida infections with tildrakizumab were low and comparable with placebo.

During the short duration of the placebo-controlled period, the frequencies of TEAEs, serious AEs and discontinuations due to AEs were comparable among the tildrakizumab doses and ETN. The frequency of treatment-related AEs was higher with ETN than with tildrakizumab or placebo, driven mainly by injection-site-related AEs. During the full trial period, the exposure-adjusted rates of TEAEs, treatment-related AEs, serious AEs and discontinuations due to AEs were all numerically higher with ETN than with the tildrakizumab doses. However, aside from injection-site reactions, the rates of prespecified AEs (e.g. MACEs, severe infections and malignancies) were comparable among the tildrakizumab doses and ETN. Injection-site reactions were notably higher with ETN.

The current analysis is limited by the short placebo exposure compared with tildrakizumab treatment, per the trial protocols. Furthermore, the number of patients receiving placebo and ETN was approximately half that of patients receiving each tildrakizumab dose. Longer-term follow-up studies are needed to determine fully the safety of tildrakizumab in regard to MACEs and malignancies. Nevertheless, up to 64 weeks of tildrakizumab treatment was well tolerated, with low rates of serious TEAEs, discontinuations due to AEs and AEs of clinical interest. There was no evidence of increased risk for AEs of interest associated with IL-17 inhibitors within the limits of cross-trial comparison. Analysis of data from long-term extension trials will provide further knowledge regarding the safety and tolerability of tildrakizumab.