Pipeline
In its therapeutic programmes, Ablynx has adopted a progressive strategy for target selection, lead generation, pre-clinical and clinical development. This strategy is designed to fully exploit the known advantages of Nanobodies®, including their cavity binding property and their ability to act in a bi-specific or bi-functional fashion. In addition, because of their exceptional stability, solubility, and small size, Nanobodies® have the potential to be specifically formulated for a number of therapeutic areas including gastrointestinal, respiratory and dermal indications.
ALX-0081 (anti-vWF Nanobody®)
Cardiovascular disease, including acute coronary syndrome (ACS) and stroke, remains the leading cause of death in western societies despite improvements in prevention, detection, and treatment. It is caused by a narrowing or blockage of the arteries due to thrombus formation on ruptured atherosclerotic plaques, preventing enough blood reaching the heart or brain. Almost 1 million Americans die of cardiovascular disease each year, which adds up to 42% of all deaths. ACS consists of myocardial infarction (MI), as well as stable and unstable angina, of which MI is the most frequently occurring indication. Currently the treatment of ACS patients consists of a mixture of different anti-thrombotic drugs. These drugs are limited in their capability to prevent arterial thrombosis and are associated with a high percentage of drug non-responsiveness and bleeding complications.
Ablynx’s lead development programme, ALX-0081, is a therapeutic Nanobody® targeting von Willebrand Factor (vWF), which will reduce the risk of thrombosis in patients with acute coronary syndrome (ACS) and thrombotic thrombocytopenic purpura (TTP). The drug has completed phase I in healthy volunteers. The results of the double-blind, placebo controlled study in 40 healthy male volunteers show that ALX-0081, was safe and well tolerated at all doses tested, with no dose limiting toxicities or serious adverse events. In the study, treatment with the Nanobody®did not result in detectable immunogenicity. The study suggests that ALX-0081 adopts at least the plasma half-life of the target, vWF. The expected anti-thrombotic activity was shown with a biomarker in all volunteers receiving at least 2 mg of ALX-0081, indicating the high potency of the drug. ALX-0081’s pharmacological activity, based on a single injection, started at the lowest dose of 2 mg and reached a maximum duration of 12 hours at a dose of 12 mg.
Following positive Phase I results announced in December 2007, Ablynx initiated a double-blind, randomized, placebo-controlled multiple dose Phase Ib study in May 2008. The study was conducted in patients with stable angina undergoing percutaneous coronary intervention (PCI). The objectives of the Phase Ib study were to determine safety and tolerance when adding ALX-0081 to a standard anti-thrombotic regimen in patients undergoing PCI and to document biological and clinical response to the therapy. It was intended to recruit up to 64 patients with stable angina for this study. However, the primary endpoint was reached and the desired pharmacological effect was demonstrated at the end of 2008 after only 25 patients had been treated. Ablynx started Phase II development of ALX-0081 in September 2009.
Through its novel, highly selective mode of action, ALX-0081 effectively prevents arterial thrombosis, without interfering with the desired haemostasis (wound healing) in the patient which results in less bleeding complications. Pre-clinical in vivo and clinical studies confirm that ALX-0081 has the unique potential to set a new standard in anti-thrombotic therapy based on its immediate onset of action, its ultra-high potency and significantly improved safety compared to the currently marketed therapies in the form of dramatically reduced bleeding complications. Ablynx has demonstrated an impressive therapeutic window for ALX-0081 based on the high efficacy and low bleeding demonstrated in primate studies, resulting in a highly attractive drug profile.
Besides the primary indication ACS and TPP, another relevant indication for ALX-0081 is ischemic stroke. It is estimated that each year more than 700,000 people suffer from stroke in the US only, resulting in 280,000 mortalities each year.
ALX-0681 ( anti-vWF Nanobody®) - subcutaneous administration
ALX-0681 is also novel "first-in-class" therapeutic Nanobodies® targeting von Willebrand factor ("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 while ALX-0681 is administered subcutaneously. ALX-0681, is a bivalent Nanobody® with a molecular weight of 28,000 daltons, designed to selectively prevent unwanted thrombus formation in vessels under high shear conditions without interfering with desirable haemostasis and, as such, to minimize bleeding complications.
Ablynx initiated a double-blind, randomized, placebo-controlled Phase I study in healthy volunteers with ALX-0681. The subjects will receive a subcutaneous injection of the novel anti-thrombotic Nanobody® that selectively targets von Willebrand (vWF) factor. The Phase I study investigates the safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeated subcutaneous administrations of ALX-0681. Ablynx will recruit up to 36 healthy volunteers for this study.
It is anticipated that subcutaneous administration of ALX-0681 will provide access to additional patient populations suffering from unwanted blood-clot formation, such as acute coronary syndrome (ACS), that are not currently addressed by the intravenous administration of ALX-0081. In addition, ALX-0681 is also being developed for the treatment of patients with thrombotic thrombocytopenic purpura (TTP).
TNF-alpha Nanobody®
Wyeth initiated a first Phase I study in healthy volunteers for a Nanobody® targeting tumour necrosis factor alpha (TNF-alpha).
Ablynx entered into an exclusive research collaboration and license agreement with Wyeth Pharmaceuticals in November 2006, a deal potentially worth $212.5 million for the successful development and commercialisation of multiple products. In addition, Ablynx is eligible to receive royalties on product sales. Wyeth has exclusive rights to develop and commercialize anti-TNF-alpha Nanobodies® developed under the collaboration. TNF-alpha is a key drug target in combating inflammation related disorders such as rheumatoid arthritis.
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