Anticoagulant drugs inhibit the ability of blood to clot or coagulate. Major indications for treatment with anticoagulants include atrial fibrillation and deep venous thrombosis. Atrial fibrillation affects about 5 million people in the Western World. Patients with atrial fibrillation have a 5% chance per year to develop an ischemic stroke – the disease accounts for 15% of all strokes in the WW - when untreated, which can be reduced to 2.5% by using anticoagulants. However, anticoagulant therapy requires extensive monitoring of patients as over-dosing induces severe bleeding complications (occurs in 0.5-5% of the patients on anticoagulants per year), whereas under-dosing – often because of the fear for bleeding - results in loss of efficacy.
Current anticoagulant drugs without exception inhibit the basal pathway of coagulation. Because of their effects on this pathway, all marketed anticoagulants impair normal haemostasis and their therapeutic window therefore is small. Targeting the system at the level of FVIII or FIX also may not be safe as genetic deficiencies of these factors result in haemophilia A or B, which are severe bleeding disorders. In contrast, persons with FXI deficiency rarely bleed and may not have bleeding episodes at all.
Recent studies indicate that although seldom necessary for normal haemostasis, FXI dependent amplification of clotting is involved in pathologic thrombus formation: FXI-deficient mice are protected against experimental thrombosis, though having a normal bleeding time. Studies in humans further support that FXI is the long sought target for safe anticoagulation. Humans with FXI-deficiency have a markedly reduced risk for ischemic stroke and deep venous thrombosis (O Salomon et al, Thromb Haemost 2011;105:269-73; Blood 2008;111:4113-4117) whereas bleeding tendency in FXI deficiency is mild or can be unnoticed. Increased levels of FXI are associated with an increased risk for cardiovascular events and deep venous thrombosis (JCM Meijers, NEJM 2000;342:696-701; DT Yang, AJCPathol 2006;126:411-5). The differential requirement of FXI in normal and pathologic coagulation predicts an improved therapeutic window for anticoagulants targeting FXI. This concept has been validated in humans with anti-sense oligonucleotides that block the synthesis of FXI (HR Buller at al, NEJM 2015;372:232-403).
Prothix is one of the very few companies having a strong IP position on targeting FXI with inhibitory antibodies. Four different murine anti-FXI mAbs developed by Prothix indeed prevented thrombosis in a mouse models whereas the bleeding time remained normal. In contrast, heparin, though as effective as anti-FXI mAbs to prevent thrombosis, prolonged the bleeding time.
Prothix considers the use of inhibitory antibodies the preferred strategy to target FXI. Antibodies are widely used now in the clinic and have favourable toxicity profiles, and can be used on demand as well as for prophylaxis. In contrast, FXI antisense oligonucleotides cannot be used on demand, and have unknown long term toxicity.
Prothix focuses on developing inhibitory monoclonal anti-FXI antibodies (anti-FXI mAb) as first in class of this type of anticoagulants. Prothix has identified a potent inhibitory anti-FXI mAb, PRO-01, which has been humanized and de-immunized. Proof of concept (PoC) was established in a FXI knock-out mouse model. Also, biochemical PoC was shown in cynomolgus monkeys. Activated Partial Thromboplastin Time (aPTT) was prolonged while prothrombin time (PT) and bleeding time ( BT) remained unchanged. A CHO manufacturing cell-line has been made to produce clinical test material.
A niche indication for PRO-01 is Vascular Access Thrombosis (VAT). VAT occurs in patients on haemodialysis because of end-stage renal disease (ESRD). Haemodialysis requires an external access to the circulation, a so-called vascular access, which, dependent on the type, has a 5-40% chance to occlude because of thrombosis. Prevention of VAT by treatment with marketed anticoagulants result in a (unacceptably) high rate of bleeding complication because kidney failure affects the function of blood platelets. Successful application in VAT will highlight the unique selling point of Prothix’s anticoagulant, which is safety. A +300mn € annual sales of PRO-01 for prevention of VAT are projected.