Low immunogenicity of emicizumab in persons with haemophilia A

Authors: Schmitt, C; Emrich, T; Chebon, S; Fernandez, E; Petry, C; Yoneyama, K; Kiialainen, A; Howard, M; Niggli, M; Paz-Priel, I; Chang, T.

Affiliations: F. Hoffmann-La Roche Ltd, Basel, Switzerland; Roche Diagnostics GmbH, Penzberg, Germany; Chugai Pharmaceutical Co. Ltd, Tokyo, Japan; Hoffmann-La Roche Ltd, Mississauga, Canada; Genentech, Inc., South San Francisco, California, USA

Publication: Haemophilia 2021; September 2021

Abstract: INTRODUCTION Emicizumab is a humanised, bispecific monoclonal antibody mimicking the cofactor function of activated factor (F)VIII. It is indicated for routine prophylaxis of bleeding episodes in persons with haemophilia A (PwHA) with/without FVIII inhibitors. AIM To evaluate the development of anti-emicizumab antibodies and their impact on pharmacokinetics (PK), pharmacodynamics (PD), efficacy and safety in PwHA. METHODS Data from seven completed or ongoing phase 3 studies were pooled. The assessment of the immunogenicity profile of emicizumab included anti-drug antibody (ADA) measurement and the association of ADAs with PK, PD, bleeding events, and adverse events. RESULTS Of 668 PwHA evaluable for immunogenicity analysis, 34 (5.1%) developed ADAs after exposure to emicizumab. ADAs were transient in 14/34 PwHA (41.2%). ADAs were neutralising in vitro in 18/34 PwHA (52.9%) and associated with decreased emicizumab concentration in 4/668 evaluable PwHA (.6%); of those, one (.1%) discontinued emicizumab due to loss of efficacy. ADAs without decreased exposure did not impact emicizumab efficacy. The proportion of PwHA who had injection-site reactions (ISRs) was higher in ADA-positive PwHA (29.4% vs. 20.8%); however, the safety profile was similar between ADA-positive and ADA-negative PwHA, overall. No cases of anaphylaxis or hypersensitivity were reported in ADA-positive participants. CONCLUSION The immunogenicity risk of emicizumab in phase 3 studies was low. ADAs, including in vitro neutralising ADAs, were not associated with a change in safety profile. Routine surveillance is, therefore, not warranted; however, in cases where a loss and/or waning of efficacy are observed, prompt evaluation by a healthcare provider should be sought.