Thrombotic disorders may be characterized by a single major thrombus, frequently observed in acute ischemic stroke, in large vessels, or numerous thrombi throughout the body, as is seen in Thrombotic Thrombocytopenic Purpura (TTP) and Disseminated Intravascular Coagulation. Widespread microvascular thrombosis can lead to ischemia (tissue damage or death due to decreased blood supply) in multiple organs, ultimately resulting in organ failure. Also a major macrovascular thrombus will lead to impaired blood supply to the vessels immediately downstream of the occluding blood clot and cause tissue damage. Tissue damage is often irreversible and may lead to life-long disabilities.
Thrombotic Thrombocytopenic Purpura (TTP)
TTP is a rare disease (approximately 5 individuals per 1 million people, each year) that is characterized by sudden episodes of widespread microvascular thrombi formation. These attacks can lead to a disruption of blood flow to organs such as the kidney, heart, and brain, resulting in the functional failure of these organs. Patients with TTP attacks present with fatigue, breathing difficulties, bleeding underneath the skin or bleeding in general, and, in severe cases, neurological dysfunction leading to a seizure, stroke, or coma. TTP has a mortality of up to 90% if left untreated, and a recurrence rate of more than 1 in 3 patients experiencing a TTP attack.
TTP is caused by the deficiency of the enzyme ADAMTS13 in the human body. ADAMTS13 continually breaks down VWF, ensuring that it does not form large complexes with platelets, which can trigger pathological thrombus formation. There are two types of TTP: congenital TTP (cTTP) and immune-mediated TTP (iTTP; also known as acquired TTP, aTTP). The cause of iTTP is an autoimmune condition where antibodies against ADAMTS13 (anti-ADAMTS13 auto-antibodies) are formed that block the function of ADAMTS13. The autoimmunity causing iTTP can be triggered by several factors including infections, medications, pregnancy, and estrogen-containing birth control, or have no known cause (idiopathic). In cTTP, the absence of ADAMTS13 is caused by an inborn (congenital) genetic mutation in the ADAMTS13 gene, resulting in reduced ADAMTS13 activity.
TTP diagnosis is based on the clinical presentation of a patient, low platelet counts, and reduced ADAMTS13 activity. When also high antibody levels to ADAMTS13 are observed, the diagnosis iTTP is set. The current standard of care for iTTP patients includes multiple days of plasma exchange to remove anti-ADAMTS13 antibodies and restore ADAMTS13 activity, while immune modulation is applied in addition to reducing the development of new anti-ADAMTS13 antibodies over time. International recommendations also include the use of Cablivi® (caplacizumab), a nanobody which binds to VWF, to prevent VWF-platelet interactions and the formation of thrombi in the microvasculature. In contrast, the standard of care for cTTP includes multiple sessions of plasma infusion or exchange to provide additional ADAMTS13 and remove large VWF multimers.
The TTP mortality rate is approximately 15% per episode with the currently approved treatments, which is much lower than the 90% mortality rate if left untreated. However, patients still experience an attack duration of, on average, 3 to 4 days. During this time, patients are experiencing the harmful effects of microvascular thrombosis. Therefore, even with treatment, 50% of surviving patients endure long-term impairments related to the organ damage caused by the attack.
Preclinical models for TTP have indicated that TGD001 initiates rapid breakdown of VWF-rich thrombi and reduces tissue damage. TGD001 therefore holds the potential to reduce organ damage during a TTP attack, leading to lower volumes of plasma exchange and improved long-term patient outcomes.
Acute Ischemic Stroke (AIS)
AIS occurs when one or multiple thrombi block arteries in the brain and cause a sudden loss of blood flow to major parts of the brain. The result is a rapid onset of neurological dysfunction, producing symptoms such as confusion, numbness, language difficulties, visual problems, and a loss of balance or coordination. About 18 million people experience a stroke each year, leading to 5 million mortalities and 5 million people permanently disabled.
The current standard treatment for AIS aims to quickly restore blood flow to the affected part of the brain with the aim to limit the damage caused by insufficient oxygen supply. Two strategies are used to achieve this: thrombolytic medications, and mechanical removal of the thrombus (thrombectomy).
Existing thrombolytic medications target fibrin, which is often abundantly present in the macrovascular thrombi as observed in AIS, and activate plasmin, an enzyme that degrades fibrin.
Actilyse®, Activase® (alteplase), a recombinant tissue plasminogen activator (rTPA), is the current first-line thrombolytic used in patients with AIS. Unfortunately, less than half of patients experience a good outcome (i.e. minimal disability at three months post-stroke) after. The systemic activation of plasminogen by such rTPA increases the risk of internal brain bleeding (intracranial haemorrhage). The treatment window with rTPA is limited to 4.5 hours after the symptom onset, as beyond this timepoint the risk of bleeding outweighs the benefit of thrombolysis by rTPA. A limitation is also with the thrombus composition: it requires binding to fibrin, hence thrombi with lower fibrin compositions are less effectively broken down.
Rather than targeting fibrin, TGD001 targets the VWF in a thrombus. VWF is more consistently present in all thrombi and therefore is a more general applicable target for thrombolytics. TGD001 has shown efficacy in preclinical AIS models with both fibrin-rich and fibrin-poor thrombus compositions. In addition, targeting TGD001 to VWF in occlusive blood clots results in a localized activation of plasmin, which holds the promise to reduce systemic plasmin activation and thereby uncontrolled bleeding risks as observed with rTPA.
Mechanical thrombectomy is the second possible strategy. This is a surgical procedure to remove a thrombus from the large artery. The procedure can only be applied to the larger vessels, and only 10% of the patients with AIS are finally eligible for this therapy.
Unfortunately, not all patients have a successful restoration of normal blood flow (recanalization) following mechanical thrombectomy and only half of the patients experience good long-term outcomes. In these cases of poor outcomes (death or disability) despite recanalization, it is likely that the mechanical thrombectomy was conducted too late to salvage the tissue and/or downstream smaller vessels remained obstructed even when the major thrombus in the artery was removed.
Thrombolytic medication given before mechanical thrombectomy can improve recanalization but comes with an additional safety risk due to the associated bleeding risks. Ultimately, an improved safety profile of TGD001 compared to the currently approved thrombolytic medications would allow application in conjunction with mechanical thrombectomy. The ability of TGD001 to dissolve both fibrin- and VWF-rich thrombi, makes that occlusions in the downstream smaller vessels can also be removed.