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

Abstract

BACKGROUND:

We 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).

OBJECTIVES:

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

METHODS:

In 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.

RESULTS:

In 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.

• Authors: A B Kimball, T Kerbusch, F van Aarle, P Kulkarni, Q Li, A Blauvelt, K A Papp, K Reich, D Montgomery
• Journal: The British journal of dermatology (Br J Dermatol) Vol. 182 Issue 1 Pg. 180-189 (01 2020) ISSN: 1365-2133 [Electronic] England
• PMID: 30916381 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing
• tildrakizumab

Topics

• Antibodies, Monoclonal (adverse effects)
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing
• Humans
• Psoriasis (drug therapy)
• Treatment Outcome