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KPL-404 and autoimmune diseases mediated by the CD40/CD154 interaction

KPL-404 is a human monoclonal antibody inhibitor of the CD40/CD154 (formerly referred to as CD40 ligand or CD40L) co-stimulatory interaction. It blocks the interaction between CD40 and CD154 by binding to CD40.

The interaction between CD40/CD154 is one of the most critical co-stimulatory immune checkpoints. It plays a crucial role in T-cell-dependent B-cell activation and differentiation, steps that are necessary for an antibody-mediated humoral response. It also has an impact on dendritic cells and macrophage activity.

The CD40/CD154 interaction has been implicated in many autoimmune conditions including:

  • Rare diseases, such as ankylosing spondylitis, systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis
  • More prevalent diseases, such as rheumatoid arthritis, psoriatic arthritis, and Graves’ disease
  • Solid organ transplant graft rejection
External proof of concept (POC) has been demonstrated with other agents that inhibit the CD40/CD154 interaction by various mechanisms. Positive data over multiple disease areas are available in published literature.

KPL-404 clinical program

Kiniksa has completed a Phase 1 single-ascending dose study designed to investigate the safety and tolerability as well as the pharmacokinetic and pharmacodynamic properties of a single dose of KPL-404 administered intravenously (IV) or subcutaneously (SC) in healthy volunteers. KPL-404 was well tolerated, with no dose-limiting safety findings. The data supported testing of longer-term SC administration in patients with autoimmune disease:

  • A single administration of 3 mg/kg and 10 mg/kg IV demonstrated full CD40 receptor occupancy (RO) through Day 29 and Day 71, respectively
  • A single administration of 3 mg/kg and 10 mg/kg IV demonstrated complete suppression of the primary T-cell-dependent antibody response (TDAR) through Day 29 and suppressed TDAR to antigen rechallenge (at Day 29) through Day 43 and at least Day 57, respectively
  • A single administration of 5 mg/kg SC showed full RO through Day 43 and complete suppression of the antigen response through at least Day 29, similar to the 3 mg/kg IV dose
A Phase 2 study is ongoing in patients with rheumatoid arthritis. Rheumatoid arthritis was selected as a well-characterized autoimmune disease with decades of published clinical data across diverse mechanistic classes, allowing for objective evaluation in established endpoints in the 12-week parallel-arm POC portion of the study. The initial pharmacokinetic lead-in of the trial is designed to support characterization of chronic SC administration of KPL-404 in a patient population, and also to provide optionality to evaluate the therapeutic potential of KPL-404 across a range of other autoimmune diseases with pathologies believed to be mediated by the CD40/CD154 interaction. Kiniksa believes the high concentration liquid formulation of KPL-404 being tested in this study could provide optionality in targeting chronic diseases by enabling practical subcutaneous administration.

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