The positive Phase I data support the progression of ALX-0681 towards Phase II testing in patients with thrombotic thrombocytopenic purpura (TTP), expected to commence in Q2 2010. The anti-von Willebrand factor (vWF) Nanobody received orphan drug designation by the EMEA and the FDA for the treatment of TTP in May this year.
The Phase I study was designed to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeated subcutaneous administrations of ALX-0681. A total of 36 healthy volunteers were treated with either single subcutaneous doses of ALX-0681 ranging from 2 mg to 16 mg or daily 10 mg subcutaneous injections for 7 or 14 days.
The desired biological effect, determined by complete inhibition of a biomarker, was achieved for more than 14 days with daily injections of 10 mg of the anti-vWF Nanobody, confirming the biological efficacy of ALX-0681. The PD parameters for coagulation Factor VIII and vWF showed a fast and reversible decrease compared to pre-dose values, with normalization between 24 and 72 hours after the last administration, depending on dose. The PK profile remained unchanged after multiple administrations, confirming the favourable pharmacological behaviour of ALX-0681.
ALX-0681 is being developed for the treatment of patients with TTP. It is also anticipated that the subcutaneous administration of ALX-0681 will provide access to additional patient populations suffering from unwanted blood-clot formation, such as those with acute coronary syndrome (ACS), which are not currently addressed by the intravenous administration of ALX-0081.
ALX-0081 and ALX-0681 are novel ’first-in-class‘ therapeutic Nanobodies targeting von vWF, a protein found in the blood that acts at a very early stage in the coagulation cascade (namely, platelet adhesion), in contrast to currently available anti-platelet drugs, which act only in the late stage of platelet aggregation. ALX-0081 is administered intravenously, whereas ALX-0681 is administered subcutaneously.
Ablynx believes that ALX-0681 and ALX-0081 might provide a solution to cardiologists’ current dilemma in ACS, which typically involves achieving a balance between the prevention of unwanted blood clots and potentially life-threatening bleeding complications. ALX-0081 and ALX-0681 could, potentially, prevent arterial thrombosis after angioplasty, which is a serious clinical problem. Other potential indications for ALX-0081 and ALX-0681 include TTP, myocardial infarction and stroke.
TTP is a disease related to the formation of white clots. The underlying abnormality in TTP is the formation of small platelet clots, which leads to occlusions of small vessels throughout the body, particularly within blood vessels supplying the brain and the kidneys. It has been shown that these small platelet clots are caused by the presence of large clusters or strings of activated vWF. Approximately four cases of TTP per million inhabitants are diagnosed per year in Europe and the United States. There is currently no approved drug therapy for TPP, and plasma exchange is the only available treatment for these patients today. Plasma exchange involves the removal of the patient’s plasma (the non-cellular component of blood) and its replacement with donor plasma. TTP remains a condition with extremely high morbidity and mortality, even with timely plasma exchange, and there is still a significant unmet medical need for this disease.