Supervisors info:
Πολίτου Μαριάννα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Κακίσης Ιωάννης, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Γιαλεράκη Αργυρή, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Thromboembolic disease remains a major source of morbidity and mortality, given that it accounts for 1 out of 4 deaths worldwide. Although anticoagulants are considered as a cornerstone for the antithrombotic practices, the most common adverse event related with the available anticoagulants is bleeding. As a result, the clinical development of a potent anticoagulant without considerable bleeding risk seems to be kind of α holy graal for industry and scientific society. In this context, FXI inhibition seems to be a promising treatment alternative and it is expected to overcome the limitations of existing anticoagulants. Preclinical data (animal models), epidemiological data (individuals suffering from hemophilia C are protected from thrombosis without any increased bleeding risk), insights about the role of FXI through the coagulation cascade and recent clinical data enhance our expectations considering FXI as a potential therapeutic target.
Activated FXI (FXIa) is a serine protease while FXI is its inactive zymogen. The structure of FXI protein is thought to be unique among all proteases involved in the coagulation cascade. The FXI protein molecule is a homodimer weighting 160kDa and consisting of two identical subunits. Specific binding sites for macromolecules such as heparin, FIX and FXII are located on each subunit. Heparin binding site plays an important role in the allosteric regulation of the protease activity. Besides the major biological function of FXI, which is activation of FIX to FIXa, additional functions, such as inhibition of fibrinolysis, render FXIa a key enzyme regarding coagulation and inflammation.
Both hemostasis and pathological thrombosis are two distinct entities with remarkably different pathogenetic mechanisms. According to the current cellular model, which has successfully replaced the classical coagulation cascade model, FXI plays a major role in the amplification of the pathological thrombus, while plays a minor role in the initiation of thrombus formation. FXI secondary role in hemostasis is consistent with the following finding: consolidation of the hemostatic plug is sufficient even if FXI levels are 10-20%. An anticoagulant which disrupts hemostasis would be followed by hemorrhagic adverse events. However, FXI inhibition is expected to reduce thrombotic episodes without affecting hemostasis and, thus, without increasing bleeding risk. To summarize, FXI inhibition uncouples thrombosis from hemostasis.
Al-Horani et al reviewed the patent literature and peer-reviewed literature for agents targeting FXI/FXIa. Both reviews include the following classes of FXI inhibitors: small peptidomimetics targeting the active site, polymeric glycosaminoglycans (GAGs) and their mimetics, sulfated nonpolymeric GAG mimetics targeting allosteric site (heparin binding site), polypeptides (natural inhibitors) which are isolated from snakes, nematodes, bats and ticks, antisense oligonucleotides (ASOs) (e.g. ISIS 416858), monoclonal antibodies (e.g. MAA868 [aka abelacimab], BAY1213790 [aka osocimab], AB023 [aka xisomab 3G3]) and aptamers (e.g. FELIAP). Enlightening the candidate anticoagulants safety profile, tolerability, pharmacokinetics and pharmacodynamics, both reviews represent a proof-of-concept regarding the feasibility of FXI(a) therapeutic targeting.
Except for natural inhibitors and aptamers, which have not reached clinical development yet, classes of FXI inhibitors currently in clinical development are the following ones: (1) ASOs, (2) monoclonal antibodies, (3) small molecules (e.g. BMS-962212, asundexian, milvexian, SHR2285, EP-7041 [aka frunexian], ONO-7684). ASOs targeting FXI are administered subcutaneously and characterized by limited glomerular filtration and limited renal clearance. Three to four weeks are necessary to produce an apparent anticoagulant effect, while ASOs can be administered once monthly given their long half-life. Monoclonal antibodies have the potential either of subcutaneous or intravenous administration. Their onset of action is rapid and their half-time is enough long (several weeks) for a monthly administration to be possible. They are characterized neither by liver metabolism nor by renal clearance. Small molecules have rapid onset and offset of action due to their low molecular weight. As a result, quite frequent administration, either once or twice daily, is required. However, administration route can be the oral one.
Phase 2 clinical trials about FXI inhibitors are classified according to the corresponding clinical settings: (1) total knee arthroplasty (e.g. FOXTROT, FXI-ASO TKA, ANT-005 TKA, AXIOMATIC-TKR) (2) atrial fibrillation (e.g. PACIFIC-AF), (3) acute non-cardioembolic ischemic stroke (e.g. PACIFIC-Stroke, AXIOMATIC-SSP), (4) acute myocardial infarction (e.g.PACIFIC-AMI), (5) end stage renal disease requiring hemodialysis, (6) other clinical settings (e.g. Covid-19, cancer). The encouraging findings derived from these four clinical trials regarding FXI inhibition through the orthopedic surgery setting, were confirmed by a meta-analysis published in 2022. On the contrary, another meta-analysis, published in 2023 at Thrombosis and Haemostasis and including these 8 randomized controlled trials we have just referred, moderates the enthusiasm stemmed from the initial findings.
However, numerous findings originated from multiple scientific approaches, including the on-going phase 3 clinical trials (e.g. OCEANIC-AF, OCEANIC-Stroke, LIBREXIA-Stroke, LIBREXIA-AF, LIBREXIA-AMI), agree on FXI inhibitors being a paradigm-shift expected to revolutionalize antithrombotic strategies.
