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

Patients and Methods

Trial Designs

Pooled data from three multicentre, international RCTs – P05495 (phase II, NCT01225731), reSURFACE 1 (phase III, NCT01722331) and reSURFACE 2 (phase III, NCT01729754) – were included in this analysis. The trial details and primary results have been previously described.[6,9] Patients in all three trials had moderate-to-severe plaque psoriasis defined as ≥ 10% body surface area involvement, Physician's Global Assessment ≥ 3 and Psoriasis Area and Severity Index (PASI) ≥ 12. Exclusion criteria related to safety outcomes are listed in Appendix S1 (see Supporting Information).

In the P05495 trial, patients in part 1 (weeks 1–16) received subcutaneous tildrakizumab 5 mg, 25 mg, 100 mg or 200 mg, or placebo at weeks 0 and 4 (Figure S1a; see Supporting Information). In part 2 (weeks 16–52), patients were rerandomized to various tildrakizumab doses based on responder status. In the reSURFACE 1 and 2 trials, patients in part 1 (weeks 1–12) received subcutaneous tildrakizumab 100 mg or 200 mg, or placebo at weeks 0 and 4 (Figure S1b, c; see Supporting Information). In reSURFACE 2, etanercept (ETN) 50 mg administered twice weekly during part 1 was an additional treatment arm. Patients receiving placebo in part 1 of reSURFACE 1 and 2 were rerandomized to tildrakizumab 100 mg or 200 mg and received tildrakizumab at weeks 12, 16 and 28 and every subsequent 12 weeks. Patients receiving tildrakizumab in part 1 continued their originally randomized treatment and received a dose of study medication at week 16, and the patients in reSURFACE 2 who received ETN in part 1 continued their ETN treatment, but administered once weekly. Patients in part 3 (weeks 28–64 in reSURFACE 1 and weeks 28–52 in reSURFACE 2) were rerandomized to tildrakizumab 100 mg or 200 mg (or placebo in reSURFACE 1) based on responder (PASI ≥ 75; ≥ 75% improvement from baseline) and partial responder (PASI 50 to < 75) status and received treatment every 12 weeks. Responders in the ETN arm in reSURFACE 2 were discontinued at week 28; partial (PASI 50 to < 75) and nonresponders (PASI < 50) were assigned to tildrakizumab 200 mg. Each trial had a 20-week follow-up period after treatment completion or discontinuation.

Supporting Figure Legend.

Psoriasis. Trial designs. D/C, discontinued; ETN; etanercept; NR, nonresponder; PR, partial responder; R, responder; TIL, tildrakizumab. *NR in P05495 was defined as PASI ≤75. In reSURFACE 1 and 2, NR was defined as PASI <50 and PR was defined as PASI ≥50 to <75.

Safety Assessments

A serious AE was any AE that resulted in death, was life threatening, required hospitalization or prolongation of existing inpatient hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, was a cancer, was associated with an overdose or was considered another important medical event.[22] Confirmed MACEs included nonfatal myocardial infarction, nonfatal stroke, and cardiovascular deaths that were confirmed as 'cardiovascular' or 'sudden'. All deaths and serious cardiovascular events were adjudicated by an external clinical adjudication committee. Severe infections were those that met the regulatory definition of a serious AE or required intravenous antibiotics. Prespecified events of clinical interest for the pooled analyses included severe infections, malignancies, nonmelanoma skin cancer, melanoma skin cancer, MACEs, injection-site reactions and drug-related hypersensitivity reactions.

Data Analysis

Data pools of treatment-emergent AEs (TEAEs) for the placebo-controlled period and full trial period (52 weeks for P05495 and reSURFACE 2; 64 weeks for reSURFACE 1) were analysed. In the full trial period pool, patients who received multiple treatments were counted in each treatment received after adjustment for exposure. For patients who dropped out during the trial and entered the follow-up period, AEs occurring during the follow-up were included and were attributed to the last treatment received. Frequencies (patients with events divided by number of patients exposed) were calculated for safety outcomes in the placebo-controlled period. Exposure-adjusted rates (patients with events per 100 patient-years) were also calculated for specific AEs in the placebo-controlled period and for safety outcomes in the full trial period. Differences and 95% confidence intervals in frequencies between tildrakizumab treatments and placebo for the prespecified events of clinical interest in the placebo-controlled period were calculated based on the Miettinen and Nurminen method[23] with no information on strata included.