Pipeline

Anti-von Willebrand Factor (vWF) programmes (ALX-0081 and ALX-0681) 
vWF acts at a very early stage in the blood clotting cascade by controlling platelet adhesion and aggregation and it represents a potential novel anti-thrombotic target in cardiovascular disease. The anti-vWF Nanobody programme is comprised of an intravenous (ALX-0081) and a subcutaneous form (ALX-0681) of a humanised bivalent Nanobody that inhibits the interaction of vWF with the GP1b receptor on platelets. Due to its small size and flexible format it is able to interact with multiple binding domains on the vWF protein, resulting in high potency. 

vWF in Acute Coronary Syndrome (ACS) 
In September 2009, Ablynx commenced a Phase II clinical trial with ALX-0081 in “high risk” patients with ACS undergoing a percutaneous coronary intervention (PCI) procedure.  This study compares ALX-0081 head-to-head with ReoPro^® (abciximab) as adjunctive therapy to a PCI procedure. All patients will receive standard anti-thrombotic therapy (aspirin, heparin and Plavix^®) and, in addition, are randomly assigned to receive either ALX-0081 or ReoPro^®. The primary endpoint of the Phase II trial is the number of bleeding events and the goal is to show a significant reduction in these events for ALX-0081 compared to ReoPro^®.  In November 2011, Ablynx reported that ALX-0081 didn’t meet its primary endpoint in the Phase II study and that both ALX-0081 and ReoPro^® have comparable bleeding profiles. The Phase II results demonstrate that ALX-0081 has an acceptable safety profile.

vWF in Thrombotic Thrombocytopenic Purpura (TTP) 

vWF is also implicated in thrombotic thrombocytopenic purpura (TTP), a rare disease where pre-cursors of vWF (ultra-large vWF multimers; UL-vWF) are present in the blood of patients and lead to blood clot formation and potentially life-threatening pathology. 

Ablynx initiated a Phase I clinical trial in 36 healthy volunteers in December 2008 for ALX-0681, the subcutaneously administered anti-vWF Nanobody product, which was successfully concluded in August 2009.  The objective of the trial was to test single and multiple subcutaneous administrations of ALX-0681 for safety, tolerability, pharmacological profiling and biological effectiveness. Overall, treatment with ALX-0681 was safe and well-tolerated and did not result in any significant bleeding events. Volunteers were monitored for 45 days after treatment and no anti-drug immune responses were detected. 

In September 2010, Ablynx initiated a Phase II study with ALX-0681 in TTP patients undergoing plasma exchange. Anti-vWF or placebo is administered as an adjunct to standard plasma exchange therapy and the primary endpoint of the study will be ‘duration until normalisation of the platelet count’ in these patients. The goal of this trial is to demonstrate a significant reduction in this endpoint in the anti-vWF treated population. It is expected that this could translate into a reduction in the number of plasma exchange days and the amount of plasma product administered. Data from this study are expected in 2013. 

Ablynx’s vWF programme was granted orphan drug status for the treatment of TTP by both the EMA and the FDA in May 2009. Orphan designation rewards the development of therapeutic drugs in rare disease indications with a significant reduction in user fees and waived costs for new drug applications and scientific advice procedures. In addition, upon receiving marketing authorisation, ten years of market exclusivity in Europe and seven years in the United States is granted for such designated commercial products. 

 
Anti-TNF programmes (ATN-103 and ATN-192) 
In 2006, Ablynx licensed the worldwide development and commercialisation rights to the anti-TNF-alpha Nanobody programme to Wyeth (acquired by Pfizer in 2009). In November 2011, Ablynx regained the rights from Pfizer to these Nanobodies targeting TNF-alpha.

Since 2009, a total of 456 subjects have been recruited in clinical trials with ATN-103 to evaluate the safety, pharmacology and clinical effectiveness in single and multiple ascending dose studies. Two single-dose studies in healthy volunteers have been completed in Japan and the US and two multiple dose studies in patients with active rheumatoid arthritis adding ATN-103 or placebo to a methotrexate background were conducted in Japan and North America/Rest of the World. First clinical proof-of-concept was generated for ATN-103 in May 2011. A dose of 80mg administered as single subcutaneous injection every 4 weeks to patients with active RA on a stable background of methotrexate resulted at week 16 in a statistically significant improvement of disease scores such as ACR20, DAS28, ACR50 and EULAR response compared with the respective placebo treatment. This study recruited a total number of 253 patients in North America/Rest of the World. No dose limiting toxicity was observed and clinical side effects did not increase significantly upon increased dosing. 2% of subjects treated with ATN-103 were positive for neutralizing anti-drug-antibodies and there were no additional observed effects on PK/PD.

In February 2010, Pfizer started a long-term safety study for ATN-103, which is an open-label extension study of the Phase II trials, that is currently ongoing at 67 centres worldwide. This trial is expected to complete during the first half of 2012. A second anti-TNF-alpha Nanobody product, ATN-192 (formerly known as PF-05230905) is expected to generate Phase I data during the first half of 2012.

 
Anti-RANKL programme (ALX-0141) 
ALX-0141 specifically targets RANKL, a key mediator of bone resorption and an essential regulator of osteoclasts, the cells involved in the breakdown of bone. ALX-0141 has been designed to inhibit bone loss associated with post-menopausal osteoporosis, RA, cancer and certain medications, and to restore the balance of healthy bone metabolism. Ablynx expects some of the unique properties of ALX-0141 (small size and less ability for cross-linking) will differentiate the product relative to other anti-RANKL products such as denosumab (Prolia^®). 

In December 2009, Ablynx started a Phase I clinical trial in 42 healthy, post-menopausal, female volunteers. The Phase I study was designed to assess safety and tolerability of a subcutaneous injection of ALX-0141 versus placebo. In addition, serum levels of certain bone biomarkers were measured to provide an early indication of biological efficacy.  Preliminary Phase I data were published in the third quarter of 2010. ALX-0141 was well tolerated and no serious adverse events or dose limiting toxicity occurred. No significant difference in the number and severity of adverse events was reported for subjects receiving ALX-0141 compared with placebo. All treatment related adverse events were of mild intensity, resolved within the study period and did not result in withdrawal of a subject from the study. 

Due to the unexpectedly prolonged drug effect in a large proportion of the subjects (as measured by levels of the bone biomarker CTX-1), the follow-up interval of the study has been extended and interim data from the nine and twelve months follow-up period were presented at EULAR in May 2011.  

 
Anti-IL-6R programme (ALX-0061) 
ALX-0061 is a Nanobody which targets the interleukin-6 receptor (IL-6R), thus disrupting the IL-6 signaling pathway. ALX-0061 inhibits the binding of IL-6 to both the membrane-bound and soluble forms of the IL-6 receptor. In contrast to the bivalent binding of tocilizumab (Actemra^®), which is marketed by Roche and Chugai, ALX-0061 interacts monovalently with these receptors and therefore does not possess the potential to induce unwanted side-effects associated with cross-linking of the two receptor types. The product also does not have an Fc (‘antibody tail’) component and therefore is not expected to activate antibody dependent cellular cytotoxicity and hypersensitivity reactions which can occur with monoclonal antibodies. 

ALX-0061 comprises a humanised and sequence optimised Nanobody in a monovalent IL-6R targeting half-life extended format. Based on pre-clinical data, Ablynx believes that ALX-0061 has the potential to show an improved safety profile compared with the benchmark monoclonal antibody. In addition, the smaller size of ALX-0061 is expected to provide an advantage in terms of increased tissue penetration compared to the larger monoclonal antibody. 

During the course of 2009, Ablynx successfully completed a proof-of-concept study for the anti-IL-6R programme in an in vivo model representative of an acute inflammatory condition. Based on this data, ALX-0061 was selected to progress into pre-clinical development. Ablynx has submitted a request for clinical trials authorisation (IMPD) in December 2010 and initiated a Phase I/II clinical trial in 70 patients with rheumatoid arthritis in March 2011. End November 2011, positive interim data from this study (single ascending dose part) were published, and the multiple dose part (Phase II) of this study was initiated. 

 
Anti-RSV infection programme (ALX-0171) 
ALX-0171 is a Nanobody product which binds to RSV and neutralizes the virus. Like many Nanobodies, ALX-0171 is very stable with a low propensity to aggregate, making it suitable for inhalation. It can also be manufactured at relatively low cost in microbial systems. ALX-0171 is the first Nanobody to enter the clinic that will be administered through inhalation instead of injection. It has the potential to be the first in class RSV therapeutic. 

ALX-0171 was selected as a pre-clinical candidate in March 2010. ALX-0171 has the potential to be effective both in the prevention of RSV infection as well as in treatment once infection has occurred. It is Ablynx’s first Nanobody candidate to be delivered through a route other than injection: via the lungs. In December 2011, the programme entered Phase I clinical trials in healthy volunteers. 

 
Anti-CXCR4 programme (ALX-0651) 
ALX-0651 is Ablynx’s first biparatopic Nanobody against a GPCR, a target class that is notoriously difficult to reach using conventional antibodies. ALX-0651 comprises two humanised and sequence optimised Nanobodies which bind to different epitopes on CXCR4 (biparatopic structure with a 100x increased potency) and is a potent antagonist of the CXCR4/CXCL12 axis. When the interaction of CXCR4 with CXCL12 is blocked, stem cells are released from the bone marrow into the peripheral blood where they can be collected for use in patients with certain malignancies who require stem cell transplantation. 

ALX-0651 is highly selective for CXCR4 and is therefore expected to be safe and well tolerated, so that it can be used in first line treatment of patients undergoing hematopoietic stem cell mobilization (usually via multiple mobilization procedures). Ablynx has demonstrated in vivo proof-of-concept in a hematopoietic stem cell model, where a single, intravenous administration of a formatted anti-CXCR4 Nanobody resulted in rapid mobilisation of stem cells, with a sharp and predictable peak which indicates the Nanoboy’s high potential to harvest stem cells with a limited number of apheresis procedures. In June 2011, Ablynx initiated a Phase I clinical trial in healthy volunteers with ALX-0651 and ALX-0651 is the first Nanobody in clinical trials targeting a GPCR, a target class that has proven to be difficult to address with conventional antibodies. Data from this study are expected during the first half of 2012.