Pipeline

Anti-von Willebrand Factor (vWF) Nanobody caplacizumab to treat Thrombotic Thrombocytopenic Purpura (TTP)

vWF is 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.  There are currently no drugs specifically approved for the treatment of TTP.

Ablynx is developing its anti-vWF Nanobody for the treatment of acquired TTP, which is a combination of intravenous and subcutaneous dosing of the same therapeutic Nanobody. The Company is currently testing caplacizumab in an international Phase II clinical trial, and the aim is to complete recruitment by the end of 2013.

Ablynx’s vWF programme was granted orphan drug status for the treatment of TTP by both the EMA and the FDA in 2009, providing a period of market exclusivity upon approval.

Related presentations, abstracts and posters

ALX-0681 is safe and efficacious in a baboon model of acquired TTP

17th Congress of the European Hematology Association: webcast

Anti-TNFα Nanobody (ozoralizumab (ATN-103)) to treat rheumatoid arthritis
Ozoralizumab is a trivalent, bi-specific Nanobody that potently neutralises TNFα and binds to serum albumin to increase its in vivo half-life.

Clinical proof-of-concept (POC) was achieved in May 2011 in patients with active rheumatoid arthritis (RA). A dose of 80 mg administered as a single subcutaneous injection every four 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 POC 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 ozoralizumab were positive for neutralizing anti-drug-antibodies and there were no additional observed effects on PK/PD.

Results from a long-term (48 weeks) safety study for ozoralizumab, which is an open-label extension study of the Phase II trials, demonstrate that ozoralizumab could have an important competitive and differentiated position in the TNFα market. Ozoralizumab potentially enables individualised treatment and neutralising anti-drug antibodies against the Nanobody do not impact the efficacy of the Nanobody.

Ablynx is currently looking for a partner to bring ozoralizumab to the next step of clinical development and beyond. For further information, please contact , Chief Business Officer.

Related presentations, abstracts and posters

2012 American College of Rheumatology Annual Meeting – 10-14 November 2012
poster #1311: A novel individualised treatment approach in open-label extension study of ozoralizumab (ATN-103) in subjects with rheumatoid arthritis on a background of methotrexate

Superior Efficacy of Ozoralizumab, An Anti-Human TNF Nanobody in a Transgenic Mouse Model of Polyarthritis.
Presentation

A Multiple Ascending Dose / Proof of Concept Study of ATN-103 (ozoralizumab) in Rheumatoid Arthritis Subjects on a Background of Methotrexate
Presentation

Pharmacokinetic-Pharmacodynamic Modeling of Ozoralizumab (ATN-103), a Novel Humanized Nanobody Tumor Necrosis Factor Inhibitor for Rheumatoid Arthritis

Anti-IL-6R programme (ALX-0061) to treat rheumatoid arthritis

ALX-0061 targets the interleukin 6 pathway via its IL-6receptor (IL-6R), which plays a fundamental role in the inflammation process in RA.

ALX-0061 has been designed to become a best-in-class therapeutic. Its small size (26kD) should allow ALX-0061 to penetrate more effectively into tissues. The potent, monovalent interaction of the molecule with its target reduces the possibility of off-target effects. Its binding to human serum albumin prolongs the in vivo half-life of the product and can lead to improved trafficking to areas of inflammation. The Nanobody has a very strong affinity for soluble IL-6R which should ensure fast target engagement and could result in a fast onset of effect. ALX-0061 appears to benefit from the general Nanobody characteristic of having a very low immunogenic potential. ALX-0061 is a very robust and stable drug product that is already manufactured at a multi-thousand litre scale. It can be administered both intravenously and subcutaneously.

In March 2011, Ablynx initiated a Phase I/II study in 64 patients with rheumatoid arthritis. In the Phase II part, 37 RA patients were recruited and were randomised to three dose groups of intravenously administered ALX-0061 (1mg/kg Q4W, 3mg/kg Q4W and 6mg/kg Q8W) or to placebo. A total of 34 patients were eligible for determination of efficacy parameters at the 12 week interim period and all these patients continued the study until week 24, and results were published on 13^th February 2013.

Depending on the patient’s disease status at week 10, the monthly dose was increased (from 1mg/kg to 3mg/kg; or from 3mg/kg to 6mg/kg) or the dosing regimen intensified (from 6mg/kg Q8W to 6 mg/kg Q4W), and patients on placebo could start monthly ALX-0061 treatment at 3mg/kg. The vast majority of patients (86%, N=24) completed the study at their ALX-0061 starting regimen (the ‘unmodified’ group), for 4 patients the dosing regimen was modified (the ‘modified’ group) and 3 patients were switched from placebo to ALX-0061 treatment (the ‘switchers’).

At all doses tested, ALX-0061 was well-tolerated and the safety profile compared favourably to data reported for other biological DMARDs. No clinically relevant neutropenia (moderate or severe decrease in neutrophils, a type of white blood cell), no clinically significant increases in lipid levels (cholesterol and triglycerides) were observed, and there were no serious infections. Infrequent elevation of liver enzymes were reported; the events were transient, generally mild to moderate, and did not result in a discontinuation of the treatment. Additionally, the side effect profile of ALX-0061 did not change with increased dose or treatment duration and no anti-drug antibodies were detected.

The efficacy results (Phase II study) for the ‘unmodified’ patient population at week 24 are presented below:

Ablynx is currently investigating the next development steps and has initiated discussions with pharmaceutical companies. In parallel, the Company is exploring how to maximise the value of the asset through additional internal development.

Related presentations, abstracts and posters

2012 American College of Rheumatology Annual Meeting – 10-14 November 2012
poster #336: Pre-clinical development of ALX-0061, an anti-IL-6R Nanobody for therapeutic use in rheumatoid arthritis with a high in vitro affinity and potency and a competitive in vivo pharmacological profile
poster #1307: Anti-IL-6 receptor Nanobody (ALX-0061) seamless “first-in-human” Phase I/II POC study in patients with active RA on stable MTX treatment

10th World Congress of Inflammation
Poster

13th Drug discovery and developmet leaders summit 2012
Presentation

Anti-RANKL Nanobody (ALX-0141) to treat bone-loss related disorders
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 is a trivalent, bi-specific Nanobody targeting RANKL and that binds to serum albumin to increase its in vivo half-life.  Ablynx successfully completed a Phase I study, and the results from this Phase I trial, including the one year follow-up information, indicate that ALX‑0141 is well tolerated and can be administered safely over a wide range of doses. All treatment related adverse events were of mild intensity, resolved within the study period and did not result in any withdrawals. Even at the lowest dose, ALX‑0141 exhibited a strong and sustained inhibitory effect on bone resorption markers.
Ablynx is currently looking for a partner to bring ALX-0141 to the next step of clinical development. For further information, please contact , Chief Business Officer.

Related presentations, abstracts and posters
Competitive pharmacological and pharmadynamic profile of ALX-0141
Poster presented at American Society for Bone and Mineral Research in 2010 and 2009

Phase I data presented at EULAR in 2011

ALX-0141 increases bone mass in cynomolgus monkeys
Presentation at ECTS 2012

Anti-RSV Nanobody (ALX-0171) to treat Respiratory Syncytial Viral (RSV) infections
ALX-0171 is a trivalent non-half-life extended Nanobody that specifically binds to and neutralises RSV. ALX-0171 has first-in-class potential as there are currently no drugs specifically approved for the treatment of RSV. It is the first Nanobody treatment developed for delivery directly into the lungs by inhalation. A Phase I study in healthy male volunteers demonstrated that the inhaled Nanobody was well tolerated and that no dose-limiting toxicity occurred and there was no treatment emergent immunogenicity observed. Additional Phase I studies are planned before moving into a pediatric Phase II trial.

Related presentations, abstracts and posters
Poster presentation: SOT 52nd Annual Meeting & ToxExpo (San Antonio (TX), USA)
Poster presentation: Eigth International RSV Symposium (Santa Fe) 2012
Next Generation Protein Therapeutics Summit 2012

Anti-IgE Nanobody (ALX-0962) to treat severe allergic asthma
ALX-0962 is a monovalent 26kD Nanobody which incorporates Ablynx’s proprietary plasma half-life extension technology targeting serum albumin. It has a unique dual mode of action in which it binds with high affinity to immunoglobulin E (IgE) as well as displacing receptor bound IgE. As a result, it is a very potent inhibitor of the biological effects exerted by IgE. Its high solubility allows for convenient subcutaneous administration. ALX-0962 has been developed with the potential to treat a broader population of patients suffering from asthma in a more effective and more convenient way compared to currently available therapies.

Ablynx recently initiated preclinical development with ALX-0962 with the goal to start a Phase I clinical study during the second half of 2014.