Abstract Number: OC 32.3
Meeting: ISTH 2021 Congress
Background: Concizumab (anti-tissue factor pathway inhibitor [TFPI] monoclonal antibody) is in phase 3 clinical development as a once-daily, subcutaneous prophylaxis for hemophilia A/B (HA/HB) with/without inhibitors. Like with other therapeutic antibodies, treatment may elicit an immunogenic response leading to anti-drug antibody (ADA) formation.
Aims: Investigate concizumab ADA clinical impact in phase 2.
Methods: In explorer4 (HA/HB with inhibitors) and explorer5 (HA without inhibitors), binding ADA analysis was performed with a highly sensitive and drug-tolerant bridging electrochemiluminescence assay. Confirmed positive samples were further characterized for neutralizing activity using a modified TFPI functionality assay. Immunogenicity data were assessed in relation to bleeding pattern, concizumab concentrations, free TFPI and safety parameters. Results from the trial main and extension parts are presented (≥76 weeks of treatment).
Results: In explorer4, 6/25 patients developed concizumab-binding ADAs; 5 patients had low-titer binding antibodies with no significant changes in bleeding pattern, concizumab and free TFPI levels, adverse events (AEs) or coagulation laboratory parameters. In 3/5 patients, antibodies were transient and decreased to below detection during the trial. One patient with low-titer ADAs, after experiencing trauma developed high-titer ADAs with in vitro neutralizing activity. This patient continued to receive concizumab, despite free TFPI restoration, reporting 2 bleeding episodes over a period of >7 months. In explorer5, transient, low-titer binding antibodies against concizumab developed in 9/36 patients, with no significant changes in bleeding pattern, concizumab levels, free TFPI, AEs or coagulation laboratory parameters. In one patient, a positive in vitro neutralizing result was recorded at one visit, with subsequent visits negative.
Conclusions: In concizumab phase 2, 25% of patients developed ADAs; the vast majority had low-titer, transient ADAs with no observed clinical effect. Only in one patient with trauma-induced high-titer ADAs, a correlation to clinical impact could be made due to free TFPI restoration; however, the clinical effect remains inconclusive.
To cite this abstract in AMA style:Hummelshøj Landsy L, Castaman G, Cepo K, Lenting P, Oldenburg J. Immunogenicity in the Concizumab Phase 2 Clinical Trials: Clinical Impact of Anti-drug Antibodies [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/immunogenicity-in-the-concizumab-phase-2-clinical-trials-clinical-impact-of-anti-drug-antibodies/. Accessed September 16, 2021.
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