APACs – potent, first-in-class therapeutics with vasculoprotective antithrombotic properties
Aplagon is developing APACs, which are first-in-class, antithrombotic therapeutics with vasculoprotective properties for the clinical management of thrombotic vessel occlusions and associated organ damage.
APACs have a number of important and unique properties. The compounds are named after their unique dual antiplatelet (AP) and anticoagulant (AC) activity. They uniquely target vascular injury sites where localized long-term antithrombotic and anti-inflammatory action occurs without a prolonged systemic effect. Among other benefits, this profile is anticipated to lead to a reduced bleeding risk compared with systemically acting antithrombotics.
Management of blood clots or thrombosis
Normally blood constantly flows smoothly through blood vessels. However, thrombosis, which is the formation of a clot inside a blood vessel, disturbs and obstructs efficient blood circulation. Thrombosis can have serious health consequences and even cause death.
Current antithrombotic therapies can be grouped into two classes: 1) Antiplatelet drugs that prevent platelet driven blood clots developing in arteries; and 2) Anticoagulant drugs that prevent blood coagulation driven clots developing in veins or those caused by heart arrhythmia, such as atrial fibrillation. In addition, there are fibrinolytic therapies which assist in dissolving clots after they form.
Under normal conditions, a vascular injury is healed via a series of specific activation, adhesion and aggregation of platelets, and subsequent coagulation activities. In some instances, these mechanisms can become exaggerated, leading to formation of a clot (thrombus).
A thrombus consists of platelets and fibrin. The optimum antithrombotic therapy should be directed towards both. None of the currently available antithrombotic drugs have both antiplatelet and anticoagulant effects. Neither do they specifically target the vascular injury area where the clot formation takes place, which are prone to inflammation that further enhances thrombus formation, and often vice versa.
This thromboinflammation is typically caused by atherosclerosis, where cholesterol, inflammatory cells and proteins accumulate at the vascular wall, enhancing the propensity to thrombosis. In addition, severe infections (e.g. COVID-19) or other inflammatory conditions (e.g. cancer or vasculitis) can trigger occlusive events at the affected vascular sites.
APACs – first-in-class heparin proteoglycan mimetics
APACs are mimics of the naturally occurring mast cell-derived heparin proteoglycans (HEP-PG). These molecules reside in the vascular wall, where they act as local antithrombotics and play a role in the body’s own defense and local tissue repair mechanisms. APACs are new molecular entities with unique functionality but are composed of established and widely-used pharmaceutical constituents, reducing the risk of unwanted adverse effects.
APACs have a number of important and unique properties compared with current antithrombotic therapies. For example, APACs have a dual antiplatelet (AP) and anticoagulant (AC) activity combined with anti-inflammatory activity, which targets the vascular injury sites when administered either locally or systemically/intravenously. This vascular targeting provides local long-term antithrombotic and anti-inflammatory action, based on interactions with von Willebrand factor (VWF), which is important in arteries and small vessels under high shear blood flow conditions.
Compared with current systemic antithrombotic combination drug strategies, APACs offer safety advantages, leading to an improved bleeding risk profile. APACs maintain the hemostatic adhesive capacity of platelets. While APAC inhibits collagen- and thrombin-induced activation, it allows other signaling pathways to stay functional, such as the ADP-route.
APACs – development status and clinical indications
Aplagon’s lead APAC therapeutic candidate is in clinical development. Aplagon is partnered with Cadila Pharmaceuticals Ltd. for the clinical development and commercialization of this APAC treatment in India. Aplagon retains all rights outside India.
Aplagon is pursuing the clinical development of APACs for selected, challenging and life-threatening indications, where currently no optimal treatments exist. These include hemodialysis access failure, COVID-19/sepsis-induced coagulopathy, and advanced peripheral arterial disease associated with critical limb ischemia and a risk for limb amputation.
APACs have potential applications across a number of therapeutic indications. Blood vessel occlusions occur at the vascular injury sites and play a key role in many diseases, including coronary artery disease, peripheral arterial disease, diabetes and severe inflammation and infections, such as COVID-19/sepsis. APACs have a powerful capacity to target the vascular injury sites and prevent blood vessel occlusions, thus reducing local inflammation.
APAC’s benefits – unique profile with multiple mechanisms of action
Dual potent antiplatelet (AP) and anticoagulant (AC) activity
- Unlike current antithrombotic therapies, which have either antiplatelet or anticoagulant modes of action, APACs have dual potent antiplatelet (AP) and anticoagulant (AC) activity. APACs also specifically target the injury sites to inhibit platelet-collagen interaction.
- This means that the dual antiplatelet and anticoagulant effect of APACs can markedly inhibit thrombosis by directly affecting both the cellular and molecular mechanisms.
- In case of accidental overdose or systemic exposure to APAC, a clinical reversal agent (protamine sulphate) is available.
Target the vascular injury site and have a prolonged local impact with a short, reversible systemic action to improve safety
- In contrast to current antithrombotic therapies, which are used systemically and can be associated with a high risk of bleeding, APACs systemic exposure is limited.
- APACs can be administered either systemically or locally at the site of vascular injury, often in association with vascular interventions. APACs target and bind to vascular structures at the injury site, to act locally. This mode of action enables potent, prolonged activity at the target site while reducing the risk of bleeding, the main side effect and safety hazard of antithrombotics. In addition, APACs have a short and reversible systemic half-life compared to many other antithrombotic therapies i.e. hours versus days.
- APACs provide vasculo-protection by sealing the inflamed blood vessel wall and inhibiting platelet-neutrophil interactions and unnecessary fibrin formation.
Anti-inflammatory activity and beneficial influence on vascular smooth muscle cells
- It is common that both overactive coagulation and inflammation will occur at vascular injury sites, reinforcing each other, and driving the progression of several cardiovascular diseases. In addition to potent and broad antithrombotic action, APACs also provide anti-inflammatory activity.
- APACs do not trigger harmful antibody formation targeting the platelet surface, nor cause heparin-induced immune complexes and thrombocytopenia (HIT), so can be used in HIT-prone patients.
- The combination of multiple mechanisms of action enables APACs to prevent and manage vascular injury and intervention-associated complications, both short and long-term. Short-term inhibition of platelets, coagulation and inflammation leads to reduced thrombosis and subsequent vascular damage. Long-term inhibition of vascular damage includes prevention of ischemic reperfusion injury, such as in the heart and kidneys, and attenuates vascular smooth muscle cell growth while enhancing their natural contractile properties.
Thrombosis refers to formation of a blood clot inside a blood vessel. Blood clots in arteries obstruct the blood flow to organs, depriving the tissue of oxygen delivery, which results in necrosis (tissue death). In veins, thrombosis impairs blood circulation, causes organ dysfunction, and the thrombus may dislodge to arteries.
Thrombosis is a leading cause of death and severe morbidity. Worldwide, one in four people die from causes related to thrombosis. Thrombosis is the main underlying cause in stroke, myocardial infarction, peripheral arterial disease, deep vein thrombosis and pulmonary embolism.
The goal of thrombosis therapy is to restore and maintain the normal flow of blood and support the body’s own system to dissolve the clot and prevent re-occlusion. Typically, this requires a surgical or catheter-based intervention to remove the blood clot and/or widen the narrowed or obstructed blood vessels.