A Pharmacokinetic and Clotting Activity Study of FVIII-PEGLip

The purpose of this study is to demonstrate that PEGylated liposomes (PEGLip) can shield FVIII from the immune system and inhibitors, and therefore provide a prophylactic FVIII replacement therapy for patients with inhibitors to FVIII.

This is an open-label multicenter trial for patients with severe haemophilia A with inhibitors to FVIII and without inhibitors as control. The trial consists of 4 periods: Screening, Stage A, Stage B and Safety Follow-up.

After signing informed consent, patients are assessed for eligibility during a Screening period lasting up to 21 days.

All eligible patients enter Stage A - Regimen estimation. The non-inhibitor patients receive a single IV injection at a dose of 35 IU/kg FVIII reconstituted with Water For Injection. Following a 4-day wash-out period, these patients as well as patients with inhibitors receive a single IV injection of FVIII-PEGLip at a dose of 35 IU/kg FVIII + PEGLip 22 mg/kg to determine the duration of haemostatic cover and therefore required injection frequency to prevent bleeds.

Stage B - multiple dosing: all patients receive injections of FVIII-PEGLip for 6 weeks at a frequency determined in Stage A for each individual patient.

Safety follow-up: 15 and 30 days after the last injection of FVIII-PEGLip, patients are contacted for any adverse events or bleeding episodes.

Eligibility Criteria:
Inclusion Criteria:

* Male adult patients aged 18 to 60 years;
* Severe Haemophilia A (FVIII plasma level \<1IU/dL) with documented history of bleeds (for at least 6 months prior to enrolment);
* For patients without inhibitors: inhibitor titre \< 0,6 Bethesda units and no medi-cal history of inhibitors;
* For patients with inhibitors: inhibitor titre ≥0,6 Bethesda units or documented medical history of inhibitors titre ≥0,6 Bethesda units;
* Adequate hematologic function, defined as platelet count ≥ 100,000/μL and hemoglobin ≥ 8 g/dL (≥ 4.97 mmol/L) at the time of screening;
* Adequate hepatic function, defined as total bilirubin ≤ 1.5 × the upper limit of normal (ULN) (excluding Gilbert's syndrome) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 ×ULN at the time of screening; no clinical signs or known laboratory/radiographic evidence consistent with cirrho-sis;
* Adequate renal function, defined as serum creatinine ≤ 2.5 × ULN and creati-nine clearance by Cockcroft-Gault formula ≥ 30 mL/min;
* Patient's written informed consent, confirming his willingness to comply with the requirements of this protocol.

Exclusion Criteria:

* Low platelet counts (\<100000 / μl);
* Congenital or acquired bleeding defects (including acquired hemophilia) other than Hemophilia A;
* Abnormal renal function (serum creatinine concentrations greater than 1.3 mg/dL);
* Active hepatic disease (persistent aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\] increases to greater than five times the upper limit of normal);
* A history of severe adverse reactions to blood products and/or plasma derived FVIII concentrates or liposomes, or PEG, or Nuwiq;
* A history of allergic reactions to bypassing agents;
* Any concomitant immunological disease (e.g. autoimmune chronic active hepati-tis, autoimmune thrombocytopenic purpura or Immune Thrombocytopenic Pur-pura (ITP), lupus, Multiple Sclerosis (MS));
* Patients receiving immunosuppressive treatment (excluding glucocorticoids);
* Patients receiving therapy with interferon;
* Patients receiving any immune tolerance induction (ITI) therapy at the moment of the screening;
* Any individual with known dyslipidemia disease or actively taking cholesterol lowering drugs for the treatment of hypercholesterolemia or hyperlipidemia (e.g., statins, cholesterol absorption inhibitors, bile acid sequestrates, nicotinic acid or fibrates);
* Intake of NSAIDs (except COX-2 inhibitors), acetylsalicylic acid (Aspirin) or any other antiplatelet agents, opioids.;
* Patients who have participated in another Clinical Trial (including medical device studies) within the past 60 days;
* Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study or that would, in the opinion of the investigator or Sponsor, preclude the patient's safe participation in and completion of the study or interpretation of the study results, according to the Investigator.
* For patients without inhibitors - a history of demonstrating long half-lives for FVIII.