Low immunogenicity of emicizumab in persons with haemophilia A

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.

Prophylactic emicizumab for hemophilia A in the Asia‐Pacific region: A randomized study (HAVEN 5)

“…Of the eight participants who developed ADAs during treatment in HAVEN 5, only one exhibited neutralizing ADAs associated with decreased emicizumab plasma concentrations, which were transient in nature 30 . No impact on efficacy or PK was observed for the remaining seven participants, and the presence of ADAs did not affect the safety profile of emicizumab.…”

A novel next‐generation FVIIIa mimetic, Mim8, has a favorable safety profile and displays potent pharmacodynamic effects: Results from safety studies in cynomolgus monkeys

“…Furthermore, in nonclinical studies with emicizumab, 30% of animals dosed for 26 weeks developed ADAs 18 . Subsequently, the overall neutralizing ADA incidence across the pivotal phase III emicizumab studies was 2.7% 20 …”

“…18 Subsequently, the overall neutralizing ADA incidence across the pivotal phase III emicizumab studies was 2.7%. 20 Local injection site observations in animals following administration of Mim8 in this study were considered related to SC dosing of Mim8 and were most likely a local immunogenic effect related to administration of a species-foreign protein to immunocompetent animals as the findings primarily occurred in the animals with detected ADAs.…”

Next generation FVIII mimetic bispecific antibody for hemophilia A

“…6 It has now been documented that anti-drug antibodies occur in up to 5.1% of hemophilia A patients treated with emicizumab. 18 No data are as yet available on the immunogenicity of Mim8; the anti-FIX arm is derived from the Kymouse model whereas the anti-FX arm is derived from a phage display library expressing human antibodies. 7 Variable and constant heavy and light chain domains of Mim8 are therefore of human origin.…”

“…It has now been documented that anti‐drug antibodies occur in up to 5.1% of hemophilia A patients treated with emicizumab 18 7 .…”