PB0312 - Assessment of post-treatment anti-drug antibodies to caplacizumab in patients with immune-mediated thrombotic thrombocytopenic purpura

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP), also known as acquired TTP (aTTP), is a rare blood disorder characterized by autoantibodies to a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13), which causes microangiopathy and hemolytic anemia. Treatment approaches for iTTP include therapeutic plasma exchange (TPE) and immunosuppressive therapy, alongside caplacizumab (a bivalent anti–von Willebrand Factor humanized single variable domain compound). TPE can complicate measurement of anti-drug antibodies (ADAs) by transferring pre-existing antibodies (pre-Abs) via donor plasma or by dilution of treatment-emergent (TE) ADAs.

Aims: To assess the presence of ADAs in patients with iTTP treated with caplacizumab during clinical trials.

Methods: Samples from four clinical trials (NCT01151423 [TITAN], NCT02553317 [HERCULES], NCT02878603 [Post-HERCULES], NCT04074187) were evaluated with four assays (Figure). The combination of ADA and modified ADA (mADA) assays allows differentiation of pre-Abs from TE ADAs, while the functional neutralizing antibody (NAb) assay and Neutralizing Epitope Characterization Assay (NECA) evaluate the neutralizing potential of detected ADAs.

Results: Immunogenicity data from 228 patients were assessed. The proportions of participants with pre-Abs ranged from 17.1% to 56.7% and incidence of drug-induced TE ADAs was 3.1% to 14.3% (Table). The proportion of patients with TE ADAs with neutralizing potential was low (NAb: 0%–12%; NECA: 2.7%–14.3%). Overall, no impact of pre-Abs, TE ADAs, or TE NAb on efficacy was observed in pivotal studies conducted in patients with iTTP and no serious adverse events were reported in patients with TE ADAs (data not shown).

Conclusion(s): A complex immunogenicity assay strategy was required to define the TE ADA and pre-Ab status of patients with iTTP treated with caplacizumab. In addition to the observed pre-Abs range from 17.1% to 56.7%, few patients were determined to be TE ADA or NAb positive, which had no impact on efficacy and safety.

Funded by Sanofi.