Prospective Controlled Monitoring of Hemlibra Prophylaxis Initiation in a Large Cohort of Hemophilia a Patients- Real World Data

Background: Hemlibra is a bispecific antibody that bridges factor IXa and factor X to restore hemostasis in patients with Hemophilia A (HA). It has proven efficacy and safety in multicenter trials. However, real world data is currently lacking. Ancillary tests' results for monitoring Hemlibra's hemostatic effect are scarce. Aim: To evaluate laboratory monitoring and any clinical correlations to hemostasis in patients with HA who initiate prophylactic treatment with Hemlibra, per standard protocol. Methods: Any severe HA patient with or without inhibitors treated by Hemlibra and followed by our National Hemophilia Center was eligible for the study, as approved by our institutional review board. The first two subcutaneous loading injections (3 mg/kg body weight given once weekly for 4 weeks) were administered in the clinic, as was the first post-loading maintenance dose (1.5 mg/kg given once weekly) injection. The patients were instructed to contact and consult the center about any trauma, bleeding or other adverse events. Bleeding episodes as well as any surgical intervention were documented. Blood samples were obtained before initiation of therapy, during the loading period (week 2), and following the initiation of maintenance therapy (week 5). Platelet-poor plasma (PPP) was obtained and activated partial thromboplastin time (aPTT), FVIII activity and inhibitor Bethesda units (BU) assay were performed. Hemlibra levels were evaluated as previously described.1 Thrombin generation (TG) was measured in PPP and thrombin peak height and endogenous thrombin potential (ETP) were calculated.2 Results: Forty patients with HA, median age 10 years (range 6 month- 76 years) were enrolled. The group consisted of 25 children and 15 adults, of whom 18 patients had FVIII inhibitors (median 16, range 1-900BU) and 22 were without inhibitors, including 9 patients with previous history of inhibitor. Patients were clinically followed for a median of 18 weeks (range 9-76 weeks). During follow-up only one patient experienced spontaneous bleeding episodes. Hemarthroses (mainly target joints) occurred in 4/40 patients (1 child only) and post traumatic bleeds were documented in 8 patients. However, 17/40 experienced trauma that did not cause any bleeding. For 32/40 patients, Hemlibra prophylaxis was sufficient to maintain hemostasis without additional supplemental therapy. Five minor surgeries were safely performed in 4 children (2/5 without supplemental therapy), yet another procedure (circumcision of a 3-months-old baby) was complicated by major bleeding. Laboratory analyses, presented as median (interquartile range), disclosed statistically significant increase of Hemlibra plasma levels from 19 (15-22) µg/ml to 50 (42-57) µg/ml between week 2 and week 5, respectively (Fig 1A). The extended aPTT values measured before treatment of 85(61-127) sec were normalized at week 2 [28 (26-30) sec] with additional significant shortening at week 5 [23 (22-25) sec; Fig 1B]. Both ETP and peak height significantly increased from baseline 43 (0-374) nM×min and 14 (6-22) nM to 700 (202-1043) nM×min and 47 (12-76) nM after 2 weeks and further to 981 (476-1396) nM×min and 72 (35-100) nM after 5 weeks; however, TG did not reach the levels observed in normal controls [ETP 1594 (1505-1722) nM×min and peak height 221 (199-273) nM]; Fig 1C,D. No differences were found between adults and children or between inhibitor and non- inhibitor patients yet notably, initial aPTT was significantly prolonged among patients with inhibitors as compared to non- inhibitor patients and the same difference persisted at week 2 and disappeared at week 5. No differences were noted between patients experiencing any bleeding or non- bleeders, probably as most bleeding episodes were trauma related. Positive correlations were found between aPTT, Hemlibra levels and TG parameters. Notably lower TG was observed in very young infants, thus interpretation of laboratory results in this age required caution. Conclusion: This study confirms the safety and efficacy of Hemlibra prophylaxis in patients with HA, including young infants. Laboratory analyses prove that Hemlibra loading, results in higher drug levels and correlates with aPTT shortening and improved TG parameters. While aPTT normalizes during Hemlibra loading, TG is still lower than the normal range observed in controls and may be a more sensitive ancillary test to predict patients' hemostasis. Disclosures Kenet: Roche: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Opko Biologics: Consultancy, Honoraria, Research Funding; CSL: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Alnylam: Consultancy, Honoraria, Research Funding; BPL: Research Funding.