Ablynx is developing a broad portfolio of Nanobody-based therapeutics that take advantage of some of the special features of Nanobodies.

These Nanobody drug candidates, which are being developed in-house and in collaboration with pharmaceutical partners, target important acute and chronic diseases across a broad range of therapeutic areas including haematology, neurology, inflammation, pulmonary diseases and oncology.

Ablynx has adopted a progressive strategy for target selection, lead generation, pre-clinical and clinical development, and is focused on retaining a balance within its pipeline of Nanobodies against known, clinically validated targets and novel, first-in-class molecules.

2014_Pipeline_EN_28 August 2014

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.

In June 2014, Ablynx achieved positive results in the Phase II worldwide TITAN study with the anti-vWF Nanobody, caplacizumab, in patients with acquired TTP. Treatment with caplacizumab plus standard of care resulted in a statistically significant reduction in time to confirmed normalisation and was associated with fewer exacerbations and more complete remissions as compared to patients receiving the standard of care plus placebo. Thus, caplacizumab could be a potential first-in-class therapy with orphan drug status for the treatment of acquired TTP.

The worldwide Phase II TITAN clinical trial was a single-blinded, randomised, placebo-controlled study which recruited from January 2011 to January 2014. In total, 75 patients were randomized on a 1:1 basis with one active drug treatment arm and one placebo arm. All patients received the current standard of care which is primarily multiple plasma exchanges. The primary endpoint of the trial was the time to confirmed platelet normalisation which guides the clinical decision to stop the daily plasma exchanges.

The results from this study showed that the group of patients treated with caplacizumab, in conjunction with plasma exchange, achieved confirmed platelet normalisation at more than twice the rate of the group receiving the standard of care plus placebo at any time during the 30-day period after start of study drug. The p-value was 0.013. Caplacizumab achieved proof-of-concept with statistically significant 39% decrease in time to normalisation of platelet count compared to placebo for patients who received no plasma exchange prior to initial treatment with caplacizumab.

The potential protective effect of caplacizumab in the treatment of TTP was also shown by the 73% fewer patients who experienced an exacerbation in the active treatment arm compared to the control group, with 3 (8%) of patients treated with caplacizumab experiencing an exacerbation compared to 11 (28%) treated with placebo. Importantly, 81% of patients achieved complete remission compared to 46% in the placebo arm and caplacizumab was generally well-tolerated, with manageable increase in bleeding tendency.

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

Ablynx’s anti-vWF Nanobody, caplacizumab, achieved clinical proof-of-concept in Phase II TITAN study
Press release
Click here to replay the webcast of 17 June 2014
pdf version of the presentation

Poster #T2111: In vitro comparability study of the biological activity and target binding of the liquid and lyophilised drug product formulation of the anti-vWF Nanobody caplacizumab (poster presented at the 2013 AAPS National Biotechnology Conference – 21 May 2013)

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 Holger Neecke, Senior Director Business Development or Cedric Ververken, Director Business Development.

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 Nanobody (ALX-0061) for the treatment of inflammatory diseases
ALX-0061 targets the interleukin 6 pathway-which plays a key role in the inflammation process in RA-by binding to the IL-6receptor (IL-6R).

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 Nanobody with its target is the basis for excellent in vivo efficacy and its high specificity reduces the possibility for 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 has shown very low immunogenic potential in the first clinical trials in patients.

ALX-0061 successfully completed a Phase IIa study in February 2013 reporting strong efficacy and safety data in patients with moderate to severely active RA on a stable background of methotrexate.

In September 2013, Ablynx and AbbVie entered into a global license agreement to develop and commercialise the anti-IL-6R Nanobody, ALX-0061, to treat inflammatory diseases.

Related presentations, abstracts and posters

2014 Annual European Congress of Rheumatology (EULAR) – 11-14 June 2014
Abstract + poster presentation: “Impact of Clinical Remission on Physical Function in Patients with Rheumatoid Arthritis Treated with ALX-0061: Post-hoc Analysis of Phase I/II Data”

2013 Annual European Congress of Rheumatology (EULAR) – 12-15 June 2013
Abstract + oral presentation: “Twenty-four weeks of treatment with a novel anti-IL-6 receptor Nanobody resulted in 84% ACR20 improvement and 58% DAS28 remission in a Phase I/II study in RA”
Abstract
+ poster presentation: “ALX-0061, an anti-IL-6R Nanobody for use in rheumatoid arthritis, demonstrates a different in vitro profile as compared to tocilizumab”

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. In October 2013, Ablynx signed an exclusive license agreement with Eddingpharm to develop and commercialise ALX-0141 in China, Macao, Taiwan and Hong Kong.

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

EULAR 2011: 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 an RSV infection in infants. It is the first Nanobody treatment developed for delivery directly into the lungs by inhalation.

An initial safety study in healthy male volunteers was successfully completed in September 2012 and demonstrated that the inhaled Nanobody was well tolerated and had no clinically relevant effect on lung function. Furthermore, no dose-limiting toxicity, no treatment emergent immunogenicity and no bronchoconstriction occurred.

ALX-0171 recently demonstrated pre-clinical proof-of-concept in a neonatal lamb model. This model is a good mimic of the infant with respect to size, breathing characteristics, lung architecture and RSV induced lower respiratory tract infection. RSV infected animals were treated once daily with inhaled ALX-0171 which led to a strong reduction in viral titres and inflammation in the lungs. ALX-0171 was also effective in improving various clinical signs and symptoms such as behavioural activity and general well-being.

In May 2014, positive results from two additional Phase I studies were obtained, following on from the successful Phase I study reported in September 2012. ALX-0171 was administered to adults via a nebulizer in a safety study and in a pharmacokinetic (PK) study.

Ablynx expects to commence a proof-of-concept study in the target paediatric population with ALX-0171 in Q4 2014 with data due in 2015.

Related presentations, abstracts and posters

Presentation: Development of ALX-0171, an inhaled Nanobody for the treatment of respiratory syncytial virus infection in infants (presented at Human Antibodies and Hybridomas Conference – 1 April 2014)
Presentation: Development of ALX-0171, an inhaled Nanobody for the treatment of respiratory syncytial virus infection in infants (presented at RSV Vaccines for the World – October 2013)
Presentation: Favorable immunogenicity profile of ALX-0171, a potent anti-RSV Nanobody, following pulmonary administration (presented at Immunogenicity Testing & Predictive Biomarkers Conference, Informa – September 2013)
Poster # M1034: Non-clinical safety assessment of ALX-0171, a Nanobody intended for clinical administration via nebulization (poster presented at the 2013 AAPS National Biotechnology Conference – 20 May 2013)
Poster #T2088: Favourable immunogenicity profile of ALX-0171, a potent anti-RSV Nanobody, following pulmonary administration (poster presented at the 2013 AAPS National Biotechnology Conference – 21 May 2013)
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

ALX-0761 is a bi-specific half-life extended Nanobody that neutralises both IL-17A and IL-17F, and which showed significantly improvement of clinical endpoints in a cynomolgus monkey RA model.

The Nanobody is currently in development by Ablynx’s partner Merck Serono, a division of Merck KGaA, Darmstadt, Germany.

Related presentations, abstracts and posters
Poster: Pre-clinical proof-of-concept of ALX-0761, a Nanobody neutralising both IL-17A and IL-17F in a cynomolgus monkey collagen induced arthritis model. (Poster presented at the Annual Meeting of the American College of Rheumatology (ACR), 26 to 30 October 2013, San Diego, California)