Thrombotic Adverse Events Frequent After Emicizumab for Hemophilia A

BongKyoo Choi, ScD, MPH, RPh

Credit: Healthy Work Campaign

Thrombotic adverse events (AEs) were more frequently reported after emicizumab treatment than for other factor FVIII products in patients with hemophilia A, according to a new analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).¹

The reporting rate of thrombotic adverse events among the total adverse event rate was approximately three times greater in emicizumab than other FVIII products, and nearly two times higher after excluding potential confounding effects of bypassing agents as co-reported drugs.

“These results suggest that the risk of thrombosis, although uncommon, but serious adverse event, may be greater in emicizumab than in FVIII products,” wrote the investigative team led by BongKyoo Choi, ScD, MPH, RPh, department of research and development at GC Biopharma.

Emicizuamb is a humanized bispecific monoclonal antibody, mimicking activated factor VIII (FVIII) to bind activated factor IX and factor X, used for prophylaxis to reduce bleeding in hemophilia A patients with and without FVIII inhibitors.² Clinical data have proven the therapy's efficacy, but there are lingering concerns about its safety.

Recent European research reported a greater thrombotic risk of emicizumab than FVIII products in patients with hemophilia A.³ However, the conclusions have not been replicated in a large database of drug adverse events from non-European countries.

The current drug safety study, using the US FDA FAERS database, sought to assess whether thrombotic adverse events are more frequent for emicizumab than other FVIII products and whether the signal is independent of bypassing agents, including activated prothrombin complex concentrate (aPCC) as co-reporting drugs.¹

Quarterly data from the FAERS database was downloaded from January 2018 to December 2022. Investigators searched the database for both the brand name and active ingredients to identify all adverse event reports of FVIII products and emicizumab as suspected drugs.

Choi and colleagues conducted disproportionality analyses for thrombotic adverse events related to emicizumab versus FVIII products. Three safety signal detection indicators were used in the analysis, ranging from proportion reporting ratio (PRR), reporting odds ratio (ROR), and informational component (IC).

Overall, investigators identified 2,383 adverse event reports for emicizumab and 9,327 adverse event reports for FVIII products in the 2018-2022 FAERS data. Upon analysis, the proportion of thrombotic events were 4.07% (97 of 2,383) and 1.44% (134 of 9,324) for emicizumab and FVIII products, respectively.

Ther reporting rate of thrombotic adverse events was significantly higher than FVIII products (PRR, 2.83; 95% CI, 2.19 - 3.66). Results with the other detection indicators were similarly higher for emicizumab, including ROR (2.91; 95% CI, 2.23 - 3.79) and IC (1.04; 95% CI, 0.70 - 1.28).

Bypassing agents were indicated as co-reporting drugs in 36% of thrombotic adverse event reports of emicizumab and 15% of the total thrombotic adverse event reports of FVIII products. After excluding thrombotic adverse event reports with bypassing agents, investigators still found the reporting proportion of thrombotic events was greater for emicizumab than FVIII products (PRR, 2.16 [95% CI, 1.59 - 2.93]; ROR, 2.19 [95% CI, 1.60 - 2.99]; IC, 0.80 [95% CI, 0.38 - 1.10]).

Given the spontaneous nature of adverse event reporting in the FAERS, by providers, industry members, and consumers, Choi and colleagues noted the possibility of underreporting and duplicated reporting of thrombotic adverse events.

“However, we think there is no evidence for any significantly under- or duplicated-reporting of adverse events between emiciuzmab and FVIII products,” they wrote. “Thus, we think that non-differential under-or-duplicated reporting of adverse events, if any, would not significantly affect the findings of the current study.”

References

1. _{Cho H, Yoo KY, Shin JY, Lee EK, Choi B. Comparison of thrombotic adverse events in patients treated with factor VIII products and emicizumab using the 2018-2022 FAERS data. J Thromb Haemost. Published online February 21, 2024. doi:10.1016/j.jtha.2024.02.009}
2. _{Kitazawa T, Shima M. Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity. Int J Hematol. 2020; 111: 20-30. 10.1007/s12185-018-2545-9}
3. _{Maria A, Alessandro C, Declan N, Peyvandi F. Hemorrhagic and thrombotic adverse events associated with emicizumab and extended half-life factor VIII replacement drugs: EudraVigilance data of 2021. J Thromb Haemost. 2023; 21: 546-52. 10.1016/j.jtha.2023.01.010.}