Assessment of the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab.

Abstract

SummaryBackgroundWe evaluated antidrug antibody (ADA) development in patients with chronic plaque psoriasis from three clinical trials of tildrakizumab, a humanized anti‐interleukin‐23p19 monoclonal antibody (P05495, reSURFACE 1 and reSURFACE 2).ObjectivesTo determine the effects of immunogenicity on the pharmacokinetics, efficacy and safety of tildrakizumab.MethodsIn 1400 (weeks 12–16) and 780 (weeks 52–64) evaluable patients randomized to tildrakizumab 100 or 200 mg, treatment‐emergent ADA‐positive (TE‐POS) patients were identified and characterized for neutralizing antibodies (NAbs). Pharmacokinetics, safety and efficacy were evaluated by ADA status.ResultsIn patients treated with tildrakizumab 100 or 200 mg continuously, < 7% were inconclusive at 52–64 weeks. In long‐term data through 52–64 weeks, the incidence of TE‐POS was 6·5% (100 mg) and 8·2% (200 mg) and the incidence of TE‐POS NAb‐POS was 2·5% (100 mg) and 3·2% (200 mg). TE‐POS NAb‐POS patients had modestly increased median tildrakizumab clearance (36·5%) compared with ADA‐NEG patients. Percentage Psoriasis Area and Severity Index improvements in TE‐POS NAb‐POS vs. ADA‐NEG patients on continuous treatment through week 52 were 76% (n = 10) vs. 91% (n = 342) for 100 mg and 77% (n = 12) vs. 87% (n = 299) for 200 mg. The incidence of potential immunogenicity‐related adverse events did not indicate a clear trend in any positive ADA patient category compared with ADA‐NEG patients through weeks 52–64. The effects of ADA on pharmacokinetics, efficacy and safety at 12–16 weeks were also summarized.Conclusions ADA development with tildrakizumab treatment for 52–64 weeks was low; around 3% of patients developed TE‐POS NAb‐POS ADAs and showed lower serum concentrations and corresponding reduced efficacy. No relationship between ADAs and safety was observed. What's already known about this topic? Unwanted immune responses – for example immunogenicity and antidrug antibodies (ADAs) – have been observed with therapeutic monoclonal antibodies and can affect efficacy and safety.Tildrakizumab is a humanized monoclonal antibody targeting interleukin‐23 and is currently approved for patients with plaque psoriasis. What does this study add? ADA development in tildrakizumab‐treated patients with psoriasis over 52 weeks was low.The small proportion of patients who had treatment‐emergent ADAs and had neutralizing antibodies experienced lower serum tildrakizumab concentrations and reduced efficacy.No relationship between ADAs and safety events was observed.