Prophylactic Treatment of Severe Haemophilia a Patients with Inhibitors to FVIII with Peglip-FVIII

Background: FVIII replacement therapy is ineffective for severe haemophilia A (HA) patients who develop inhibitors to FVIII. Patients with intractable inhibitors currently require FVIII mimetics and/or bypassing agents to prevent bleeding. A previously presented interim analysis[1] demonstrated that severe haemophilia A patients with a clinical history of developing inhibitors to FVIII could be prophylactically treated with recombinant FVIII co-injected with PEGylated liposomes (PEGLip), termed PEGLip-FVIII and may present an option for the prophylactic treatment of inhibitor patients.

Aims: To establish safety and efficacy of PEGLip-FVIII and demonstrate (a) that PEGLip-FVIII administered intravenously (IV) to severe HA patients with history of inhibitors to FVIII enhances their clotting activity and (b) that PEGLip-FVIII administered to severe HA patients with active inhibitors to FVIII enhances their clotting activity.

Methods: Stage A: Thirteen patients that were clinically defined as inhibitor patients were given single IV injections of PEGLip-FVIII (simoctocog alfa) at a dose of 22mg/kg PEGLip + 35 IU/kg FVIII and assessed for clotting activity at 0 hours (pre-injection) and at 20min, 1, 2, 4, 8, 24 hours, and daily thereafter up to 7 days using Rotational Thromboelastometry. Stage B: Patients received IV injections of PEGLip-FVIII for 6-weeks at a frequency determined by the investigator based on results obtained during Stage A. Eight of the patients had a history of developing inhibitors to FVIII but did not have active inhibitors at screening; the remaining five patients had active low-titre inhibitors at screening. Inhibitor titres were monitored throughout.

Results: Results are shown in the table.

Conclusion: Treatment with PEGLip-FVIII was well tolerated with no clinically significant changes in inhibitor titres in inhibitor patients in both groups. No adverse drug reactions were reported. The mean frequency of administration of PEGLip-FVIII was every 5.5±1.3 days. The mean number of bleeding episodes reported during Stage B was significantly reduced by 74% to 0.3±0.6 per month compared with 1.0±0.4 per month recorded during the 24 weeks prior to enrollment.

Conclusion: PEGLip-FVIII in inhibitor patients demonstrated efficacy in preventing spontaneous bleeds without increasing inhibitor titres, indicating a novel FVIII-based treatment for this cohort. The dosing interval of 5.5days at 35IU/kg represents a significant reduction in FVIII infusion frequency.

Acknowledgements: The Authors acknowledge the co-operation of the following clinicians in undertaking the study:

Nadezhda Zozulia¹, Margarita Timofeeva², Tatiana Pospelov3², Marina Kosinova⁴, Igor Kurtov⁵,Heghine Khachatryan⁶.

¹National Medical Research Centre of Hematology, Moscow.²Scientific Research Institute of Hematology and Blood Transfusion, Kirov, Russian Federation, ³State Medical University, City Hematology Centre, Novosibirsk, Russian Federation, ⁴District Clinical Hospital, Kemerovo, Russian Federation, ⁵State Medical University, Samara, Russian Federation, ⁶Haematology Center after professor R. Yeolyan, Yerevan, Armenia.

[1] Timofeeva M et al. Prophylactic treatment of severe haemophilia A patients with inhibitors to FVIII with PEGLip-FVIII. Blood 2021; 138 (Suppl 1): 1040 (abstract)

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