Caplacizumab – wholly-owned anti-vWF Nanobody to treat acquired Thrombotic Thrombocytopenic Purpura (aTTP)

  • Caplacizumab has the potential to become an important new component in the standard of care for acquired thrombotic thrombocytopenic purpura (aTTP)
  • Early October 2017, Ablynx announced positive topline results from the Phase III HERCULES study with caplacizumab:
    • Caplacizumab meets primary endpoint and key secondary endpoints
      • Statistically significant reduction in time to platelet count response, with at any given time patients treated with caplacizumab 50% more likely to achieve platelet count response
      • 74% relative reduction in the percentage of patients with aTTP-related death, a recurrence of aTTP, or at least one major thromboembolic event during the study drug treatment period
      • 67% relative reduction in the percentage of patients with aTTP recurrence during the overall study period
    • No caplacizumab-treated patients had refractory disease
    • Trend to faster normalisation of organ damage markers
    • Safety profile consistent with Phase II TITAN results and mechanism of action
    • Data will be used to drive the registration process for caplacizumab in Europe and the USA.
    • If approved by regulatory authorities, caplacizumab will be the first therapeutic specifically indicated for the treatment of aTTP
  • At 59th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, GA, USA, additional results from the Phase III HERCULES study were presented showing that treatment with caplacizumab resulted in:

    • 38% relative reduction in the number of days of plasma exchange (PEX)
    • 41% relative reduction in the volume of plasma used
    • 65% relative reduction in the number of days in the intensive care unit (ICU)
    • 31% relative reduction in the number of days in hospital
  • Caplacizumab is expected to be launched in 2018

Unmet medical need in aTTP
Acquired TTP is an ultra-rare, acute, life-threatening blood clotting disorder that leads to extensive micro-clot formation in the small blood vessels throughout the body and tissue ischaemia and damage to vital organs, including the heart, brain and kidneys. Mortality is high at 10-20%[2], with vast majority within 2 weeks post diagnosis, and about 36% of patients suffer from recurrences [1] after initial treatment with the current standard-of-care, which consists of plasma exchange (PE) plus immune-suppressive treatment. In addition, the organ damage caused by a TTP episode may result in poor longer term outcomes.
There remains a high unmet medical need to immediately inhibit the formation of microvascular thrombi, thereby reducing the risk of further organ damage. Maintenance of this platelet-protective effect is required until the underlying auto-immune activity has been resolved. Caplacizumab is being developed to address this unmet need and its clinical effect has been demonstrated in the Phase II TITAN study.

von Willebrand factor
von Willebrand factor (vWF) is a blood glycoprotein involved in haemostasis, a complex process that controls bleeding, and its primary function is to bind to other proteins, including glycoprotein Ib in the initiation of platelet adhesion.

What is the biological basis of TTP?
TTP exists in two forms: a congenital and an acquired form, with the latter accounting for >90% of the patients. The condition is characterised by severe thrombocytopenia (low blood platelet count), haemolytic anaemia (abnormal break down of red blood cells) and signs and symptoms of tissue ischemia (insufficient blood supply to organs), including stroke or myocardial infarctions. The ischemic damage may result in both acute complications as well as poor longer term outcomes. In the majority of patients, it is an autoimmune condition where auto-antibodies are generated to the enzyme ADAMTS13, which is responsible for ultra large vWF (ULvWF) cleavage. As a result of impaired ADAMTS13 activity (typically <10% of that in normal plasma), these ULvWF molecules spontaneously bind to platelets, resulting in ULvWF mediated platelet string formation in the small blood vessels.

Caplacizumab mode of action
Caplacizumab is a highly potent and selective bivalent anti-vWF Nanobody that received Orphan Drug Designation in the US and EU in 2009. It could be the first drug specifically approved for the treatment of acquired TTP.

Caplacizumab inhibits the interaction between vWF and platelets by targeting the A1 domain of vWF and thus has the potential to immediately block the ULvWF mediated platelet interactions and the formation of the string-like clots in the blood of patients with acquired TTP.

[1] George et al, 2008
[2] Scully et al, Br J Haematology 2012

Video on the results of the Phase II TITAN Study - Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura

Access the TITAN manuscript in Medical Journal – published 11 February 2016

Related publications, presentations, abstracts and posters

Presentation: "Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura", presented by Professor Marie Scully in the late-breaking abstracts session at the 59th Annual Meeting of the American Society of Hematology (ASH) in Atlanta, GA, USA

Publication: Peyvandi, F., Scully, M., Kremer Hovinga, J. A., Knöbl, P., Cataland, S., De Beuf, K., Callewaert, F., De Winter, H. and Zeldin, R. K., Caplacizumab reduces the frequency of major thromboembolic events, exacerbations, and death in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. Accepted Author Manuscript. doi:10.1111/jth.13716

Presentation: Caplacizumab may have the potential to reduce morbidity and mortality associated with acquired TTP: additional data from post-hoc analyses of the Phase II TITAN study of caplacizumab (presented at the first European Congress on Thrombosis and Haemostasis on 29 September 2016 in The Hague, The Netherlands)

Poster: Impact of caplacizumab treatment on mortality and major thromboembolic events in acquired TTP: Phase II TITAN study results (presented at the 21st European Hemathology Association Congress on 9 June 2016 in Copenhagen, Denmark)

Publication: Flora Peyvandi, M.D., Ph.D., Marie Scully, M.D., Johanna A. Kremer Hovinga, M.D., Spero Cataland, M.D., Paul Knöbl, M.D., Haifeng Wu, M.D., Andrea Artoni, M.D., John-Paul Westwood, M.D., Magnus Mansouri Taleghani, M.D., Bernd Jilma, M.D., Filip Callewaert, Ph.D., Hans Ulrichts, Ph.D., Christian Duby, M.D., and Dominique Tersago, M.D., for the TITAN Investigators, Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. DOI: 10.1056/NEJMoa1505533

Presentation: The predictive value of ADAMTS13 activity for treatment monitoring of patients with acquired TTP; data from the Phase II TITAN trial with caplacizumab (presented at the 2015 Annual Meeting of the ISTH on 24 June 2015 in Toronto, Canada)

Presentation: Additional data from the TITAN trial with the anti-vWF Nanobody, caplacizumab, in the treatment of acquired TTP (presented at the 2015 Annual Meeting of the ISTH on 24 June 2015 in Toronto, Canada)

Presentation of results of TITAN Phase II study with caplacizumab at ASH 2014
Click here to replay the webcast
pdf version of the presentation

Ablynx’s anti-vWF Nanobody, caplacizumab, achieved clinical proof-of-concept in Phase II study
pdf version of the presentation

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