Introduction: Long-term data from the HAVEN 1-4 clinical trials reaffirmed the safety and efficacy of emicizumab (HEMLIBRA®) prophylaxis in persons with hemophilia A (PwHA; Callaghan M et al. ISTH 2019 presentation). However, early data from the first Phase III trial, HAVEN 1, identified a risk for thrombotic microangiopathy (TMA) or thrombotic events (TEs) when emicizumab was used alongside activated prothrombin complex concentrate (aPCC [FEIBA]; dosed on average a cumulative amount of >100 U/kg/24 hours for ≥24 hours) leading to a warning in the label and ongoing safety monitoring. European Haemophilia Safety Surveillance (EUHASS) is a large pharmacovigilance program that monitors the safety of treatments for inherited bleeding disorders. The EUHASS registry includes real-world data on the use of emicizumab in a broad, representative population of PwHA. The objective of this analysis was to summarize thrombotic, TMA, and anaphylaxis events reported to EUHASS in association with emicizumab prophylaxis.
Methods: EUHASS is an investigator-led program with 86 participating centers in 27 countries, with centers reporting information on all the individuals they treat, thus minimizing selection bias. Adverse event data were collected from all PwHA in EUHASS who received emicizumab prophylaxis during 2018. EUHASS adverse event data are not collected according to Medical Dictionary for Regulatory Affairs (MedDRA) classification; however, for this exploratory analysis, events were coded at MedDRA preferred term level as far as possible; endpoints are provided as descriptive statistics.
Results: Data from 148 PwHA treated with emicizumab in 2018 were included in this analysis. Concurrent treatments included recombinant activated factor VII (rFVIIa; NovoSeven®; n=23 PwHA), factor VIII, (FVIII products other than Obizur®; n=9 PwHA) and aPCC (n=1 PwHA).
Two adverse events were reported in 2018 (Table 1). One event was an acute reaction (rash), reported 48 hours after dosing of a PwHA treated with emicizumab only. He recovered from the rash; the frequency was 0.7% (1/148; 95% confidence interval [CI] 0.02-3.71%). The second event was a TE-a myocardial infarction that occurred 10 hours after emicizumab dosing in a PwHA age >65 years receiving emicizumab and aPCC. The frequency of TE events was calculated as 0.7% (1/148; 95% CI 0.02-3.71%). No TMA or anaphylaxis events were reported.
Conclusions: Among PwHA treated with emicizumab at centers participating in EUHASS during 2018, only two adverse events were reported and there were no cases of TMA or anaphylaxis. While a full assessment is reserved for the final analysis, these interim real-world data are not inconsistent with the adverse event profile of emicizumab observed in clinical trials. No new or emerging safety signals for emicizumab were identified. However, this analysis was limited by the low number of emicizumab treated PwHA-especially in those without FVIII inhibitors, and relatively short exposure time to emicizumab.
Disclosures
Shang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Selak Bienz:F. Hoffmann-La Roche Ltd: Current Employment. Gadiraju:I am 50% shareholder in my own private limited company (Ravi Gadiraju Pharma Ltd): Current equity holder in private company; F. Hoffmann-La Roche Ltd, Safety Scientist (Mar 19 to current): Current Employment; Britannia Pharmaceuticals, Senior PV officer (Feb 17 to Mar 19): Ended employment in the past 24 months. Chang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Kuebler:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company.
A Bayesian meta-analytic approach for safety signal detection in randomized clinical trials
