Bleeding Events and Safety Outcomes in Pediatric Persons with Hemophilia A with Inhibitors: The First Non-Interventional Study (NIS) from a Real-World Setting

Introduction

Management of persons with hemophilia A (PwHA) with anti-FVIII antibodies (inhibitors) remains an unmet need, particularly in pediatric patients. There is a significant burden associated with treatment due to the requirement of frequent intravenous infusions; thus, a central venous access device is often required, which can lead to serious complications, such as infection or thrombosis. Emicizumab, a bispecific humanized monoclonal antibody, administered subcutaneously, bridges FIXa and FX to restore the function of FVIIIa, which is deficient in PwHA, and is being developed to prevent bleeds in PwHA with/without inhibitors. This global NIS (NCT02476942) was designed to assess real-world data (RWD) on bleed rates and current standard of treatment in PwHA and support clinical development of emicizumab; participants from the NIS can subsequently roll over to a phase 3 emicizumab study. In this abstract, we describe preliminary, prospective RWD from the NIS on bleed outcomes and hemophilia medication use in pediatric PwHA with inhibitors (Cohort B) receiving the current standard of care prior to rollover to the phase 3 emicizumab HAVEN 2 study (NCT02795767).

Methods

Eligible participants were aged <12 years with congenital HA and high-titer FVIII inhibitor history (≥5 Bethesda units/mL) previously receiving episodic or prophylactic bypassing agents; those aged ≥2 and <12 years had to have had ≥4 bleeds in 6 months prior to study entry.

Results

This preliminary analysis of Cohort B (data cutoff September 2, 2016) included 24 male pediatric PwHA with inhibitors on episodic (n=10) or prophylactic (n=14) regimens enrolled from 8 countries; median (range) age, 7.5 (2-11) years. Median observation time in the episodic and prophylactic groups, respectively, were 11.5 (5.3-22.1) weeks and 17.0 (7.7-22.6) weeks, and no participants prematurely discontinued. Previous medical conditions were reported in 9 (37.5%) participants; seasonal allergy, attention deficient/hyperactivity disorder, and dermatitis were each reported in 2 participants. For treated bleeds, annualized bleeding rates (ABRs), were 18.5 (95% CI: 11.70-29.25) and 19.4 (95% CI: 15.04-25.09) in the episodic and prophylactic groups, respectively; corresponding ABRs for all bleeds were 35.9 (95% CI: 21.94-58.89) and 36.5 (95% CI: 24.3- 54.83) (Table). There was no notable difference in the ABRs for treated or all bleeds in the episodic versus prophylactic group. Type and cause of bleeds are reported in the Table. Approximately 59% and 46% of all bleeds in the episodic and prophylactic groups, respectively, were not treated; 7 (70%) and 12 (85.7%) participants reported aPCC use, and 5 (50%) and 6 (42.9%) reported rFVIIa use (Table). Among all 24 participants, aPCC was used by 18 (75%) for treatment of bleed, 13 (54.2%) for routine prophylaxis, and 4 (16.7%) as preventative treatment before an activity; rFVIIa was used by 9 (37.5%) participants for treatment of bleed, 3 (12.5%) as a preventative dose before an activity, 2 (8.3%) for usual prophylaxis, and 2 (8.3%) as a preventative dose for procedure/surgery. At the time of data cutoff, median (range) cumulative doses of bypassing agents reported in the episodic and prophylactic groups, respectively were: 428.6 (96-3860) U/kg and 8568.5 (933-15757) U/kg of aPCC, and 1406.3 (157-3704) µg/kg and 2352.0 (632-10203) µg/kg of rFVIIa. Some participants in each treatment group received both aPCC and rFVIIa during the observation period.

Conclusion

This preliminary analysis of Cohort B in the NIS suggests that a large proportion of all bleeds in pediatric PwHA with inhibitors in the episodic and prophylactic groups were not treated. ABRs remained high even with high doses of prophylactic treatment; thus, confirming the high unmet need in the management of pediatric PwHA with inhibitors. Final data on bleed rates, hemophilia treatments, and safety outcomes (adverse events) for pediatric PwHA with inhibitors in the NIS will be presented.

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