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

Disclosures

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

In This Article

Results

Patients and Exposure

In total, 2081 patients were treated with tildrakizumab 100 mg (n = 705), tildrakizumab 200 mg (n = 708), placebo (n = 355) or ETN (n = 313) and were included in the pooled analysis. Of the 2081 treated patients, 2000 (96·1%) completed part 1 and entered into part 2 of the studies. The baseline demographics and disease characteristics of the randomized patients were similar among the treatment groups (Table 1). The mean (range) durations of exposure during the full trial period were 48 (4–76) weeks for tildrakizumab 100 mg, 47 (4–76) weeks for tildrakizumab 200 mg and 19 (4–40) weeks for placebo. The mean (range) durations of exposure with ETN were 11·4 (0·5–12·0) weeks for patients who received treatment twice weekly during part 1 and 15·4 (0·5–17·0) weeks for patients who received treatment once weekly during part 2. The total exposure was 998 patient-years for tildrakizumab 100 mg, 929 patient-years for tildrakizumab 200 mg, 219 patient-years for placebo and 153 patient-years for ETN.

Overall Safety

In the placebo-controlled period, the frequencies (patients divided by number of patients exposed) of TEAEs for tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and ETN were 48·2%, 47·9%, 53·8%, and 54·0%, respectively (Table 2). The most common TEAE in all treatment groups was nasopharyngitis (Figure 1). AEs related to the injection site were numerically higher in the ETN group than in the tildrakizumab groups or placebo group (Figure 1). Exposure-adjusted rates during the placebo-controlled period were consistent with the frequency data, confirming the higher rates for injection-site reactions with ETN compared with tildrakizumab treatment or placebo (Table S1; see Supporting Information).

Figure 1.

Treatment-emergent adverse events in ≥ 2% of patients in at least one treatment group during the placebo-controlled period (all patients as treated). AE, adverse event; ETN, etanercept; TIL, tildrakizumab; URTI, upper respiratory tract infection.

In the full trial period, exposure-adjusted rates (patients per 100 patient-years) for TEAEs for tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and ETN were 77·0, 79·3, 153·5 and 148·6, respectively (Table 2). The highest exposure-adjusted rates for treatment-related AEs, serious TEAEs and discontinuations due to AEs were observed in the ETN group, whereas the rates with tildrakizumab treatment were lower than or comparable with placebo (Table 2). Similarly to the placebo-controlled period, in the full trial period the most common TEAE in all treatment groups was nasopharyngitis, and AEs related to the injection site were highest in the ETN group.

Seven deaths, all unrelated to treatment per investigator and study sponsor assessment, occurred during or after the trials. All deaths and serious cardiovascular events were adjudicated by an external clinical adjudication committee. Additional details of these cases can be found in Table S2 (see Supporting Information).

Prespecified Adverse Events of Clinical Interest

Frequencies of confirmed MACEs, malignancies, nonmelanoma skin cancer, drug-related hypersensitivity events and severe infections in the placebo-controlled period were low, ranging from 0·0% to 0·3% among the groups (Table S3; see Supporting Information). There were no events of melanoma skin cancer in any treatment group in the placebo-controlled period. The frequency of injection-site reactions was higher in the ETN group (17·9%) than with tildrakizumab 100 mg (3·4%), tildrakizumab 200 mg (4·0%) or placebo (2·3%). The two drug-related hypersensitivity reactions in patients on tildrakizumab treatment were assessed as being due to concomitant medications. There were no statistically significant differences between tildrakizumab treatment and placebo in the frequencies of any of the prespecified AEs (Table S3).

Exposure-adjusted rates of confirmed MACEs in the full trial period ranged from 0·0 to 0·5. Exposure-adjusted rates of malignancies, nonmelanoma skin cancer and severe infections were low, ranging from 0·9 to 2·6 among the groups (Table S3). Two patients (both on tildrakizumab 100 mg) developed melanoma skin cancer in the full trial period. Both cases were determined to be melanoma in situ. With the exception of malignant neoplastic processes involving the skin, the only malignancy reported more than once in patients receiving tildrakizumab was pancreatic cancer (two cases, both with tildrakizumab 200 mg). The exposure-adjusted rate of injection-site reactions was higher in the ETN group (40·4) than with tildrakizumab 100 mg (3·5), tildrakizumab 200 mg (4·6) or placebo (5·0).

Infections

In the placebo-controlled period, frequencies of infections were comparable for tildrakizumab 100 mg and 200 mg (22·7% and 21·9%, respectively) and placebo (22·5%); all were comparable with ETN (23·6%). In the full trial period, exposure-adjusted rates for infections with tildrakizumab 100 mg and 200 mg (48·9 and 52·6, respectively) were lower than with placebo and ETN (79·5 and 86·0, respectively). In all, 33 severe infections were identified (Table 3).

One patient, a 58-year-old Asian man (birthplace unknown), had bone tuberculosis, which led to treatment discontinuation (tildrakizumab 200 mg). The patient reported occasional travel to Asia for business, but no other risk factors were noted. The original single-step Mantoux test in this patient was negative. After treatment, the tuberculosis resolved with no further sequelae. One sepsis event (tildrakizumab 200 mg) occurred 7 months after ending tildrakizumab treatment. Candida skin infections were infrequent in all treatment groups in the placebo-controlled period, at frequencies of 0·1%, 0·3%, 0·0% and 0·0% for the tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and ETN groups, respectively. Exposure-adjusted rates for Candida skin infections in the full trial period were 0·2, 0·7, 0·0 and 0·0, respectively. Oral candidiasis was also infrequent, occurring at frequencies of 0·1%, 0·3%, 0·0% and 0·0% for the tildrakizumab 100 mg, tildrakizumab 200 mg, placebo and ETN groups, respectively, during the placebo-controlled period, and exposure-adjusted rates of 0·2, 0·7, 0·0 and 0·0, respectively, during the full trial period.

Other Adverse Events of Interest

No TEAEs of new onset or exacerbation of pre-existing inflammatory bowel disease or multiple sclerosis were reported during the trials. No suicides were reported. One suicide attempt was reported in a patient who was receiving tildrakizumab 200 mg and who was on antipsychotic therapy for a known history of schizophrenia. The event was considered by the investigator to be unrelated to treatment.

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