The Use of a Pegylated Liposome in a Phase II Trial to Enhance the Potency and Extend the Dosing Interval of Prophylactic Standard Half-Life FVIII, without Increasing the Dose

Background: Prophylactic recombinant FVIII replacement therapy currently relies on the frequent intravenous (IV) administration (once every other day/2-3 times weekly) of Standard Half-Life (SHL) FVIII at a dose 20-40 IU/kg. The evolution of Extended Half-Life (EHL) FVIII has extended the dosing interval to every 4 days or 2-3 times weekly although this also relies on administering higher doses (30-60 IU/kg).

Co-formulation of a standard dose (35IU/kg) of SHL FVIII with Pegylated liposomes (PEGLip) can enhance the coagulation performance of FVIII by enhancing clotting activity and its duration of efficacy, ultimately enabling an extended dosing interval. Such benefits may also be conferred if instead of co-formulating prior to injection, the PEGLip is administered after FVIII has been injected. We have developed PEGLip ("XLR8") as the first independent adjuvant product to increase the efficacy of any SHL rFVIII, increasing their dosing intervals and providing haemostatic cover with a lower dose then is possible with current EHL rFVIII replacement products. The XLR8 adjuvant approach used with SHL factors may provide a safe, cost-effective way to reduce injection burden(potentially improving compliance) and the amount of (expensive) FVIII consumed

Aims: To demonstrate (a) that PEGLip administered intravenously (IV) to severe haemophilia A (HA) patients that have received a prophylactic dose of rFVIII immediately beforehand prolongs haemostatic cover and (b) to establish a greater dosing interval.

Methods: Stage A: Fourteen severe haemophilia A patients were given single IV injections of FVIII (simoctocog alfa) at a dose 35 IU/kg, which were followed after 15 minutes by single infusions of PEGLip 22mg/kg PEGLip 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 FVIII followed by an injection of PEGLip for 6-weeks at a frequency determined by the investigator based on results obtained during Stage A.

Results: These are shown in the table below. Treatment with PEGLip-FVIII was highly tolerated with no inhibitor generation. No adverse drug reactions were reported. The mean frequency of administration of PEGLip-FVIII was every 4.9±1.4 days. The mean number of bleeding episodes reported during Stage B was significantly reduced by 84% to 0.18±0.37 per month compared with 1.10±0.64 per month recorded during the 24 weeks prior to enrollment.

Conclusion: The separate injection of PEGLip following a standard-of-care prophylactic injection of FVIII in severe HA patients demonstrated efficacy in preventing spontaneous bleeds with an extended dosing interval of 4.9 days. Over the course of a year this could reduce the injection burden of every-other-day SHL administration by 50%, i.e. 91 injections vs. 182 injections, potentially improving patient compliance and convenience. Compared to a once-every-4-day injection of 45 IU/kg, using 35 IU/kg per administration would reduce consumption of rFVIII by 22%,

This trial has looked at the enhancement of a 4^th SHL generation, B-domain deleted FVIII. Further work is required to establish if different forms of SHL can also benefit from this enhancement and also whether it can help current EHL products to maintain homeostasis at even longer dosing intervals and lower doses.

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

Margarita Timofeeva¹, Tatiana Pospelova², Marina Kosinova³, Igor Kurtov⁴,Alexandr Myasnikov⁵,

¹Scientific Research Institute of Hematology and Blood Transfusion, Kirov, Russian Federation, ²State Medical University, City Hematology Centre, Novosibirsk, Russian Federation, ³District Clinical Hospital, Kemerovo, Russian Federation, ⁴State Medical University, Samara, Russian Federation, ⁵Republican Hospital n.a. V.A. Baranov, Petrozavodsk, Russian Federation.

Tuddenham:Biomarin: Patents & Royalties; Freeline Therapeutics: Consultancy. Ling:Ascension Healthcare plc: Consultancy. Wolf-Garraway:Ascension Healthcare plc: Current Employment.