GHENT, Belgium, 10 October 2016 - Ablynx [Euronext Brussels: ABLX; OTC: ABYLY] today announced that the first patient with acquired thrombotic thrombocytopenic purpura (aTTP), who completed the Phase III HERCULES study of caplacizumab, has rolled-over into a three-year follow-up study.
Acquired TTP is an acute, ultra-rare, life-threatening blood clotting disorder in which uncontrolled platelet aggregation and microclot formation cause small blood vessel occlusions throughout the body  , resulting in thrombotic complications and widespread organ damage  . Despite the current standard-of-care treatment of daily plasma exchange (PEX) and immunosuppression, episodes of aTTP are still associated with a mortality rate of up to 20%, with most deaths occurring within 30 days of diagnosis  . Furthermore, patients are at risk of acute thromboembolic complications (e.g. stroke, venous thrombosis and myocardial infarction) and of recurrence of disease. In addition, some patients are refractory to therapy  , which is associated with a very poor prognosis for survival of an acute episode of aTTP. Long term, patients are at increased risk of hypertension, major depression, and premature death.
The objectives of this study are to evaluate the long-term safety and efficacy of caplacizumab and repeated use of caplacizumab, and to characterise the long term impact of aTTP. Patients will attend twice yearly visits and undergo a number of clinical, cognitive, and quality of life assessments. Safety laboratory parameters, immunogenicity of repeated treatment with caplacizumab and disease-related markers will be evaluated.
Upon any recurrence of acquired TTP, standard-of-care treatment consisting of daily plasma exchange (PEX) and immunosuppression will be initiated together with open-label caplacizumab. Patients will receive an intravenous bolus injection of caplacizumab at the start of PEX treatment followed by daily subcutaneous injections for the duration of daily PEX and for 30 days thereafter. Treatment with caplacizumab may be extended in the case of persistent signs and symptoms of underlying disease (e.g. ADAMTS13 activity profile remains below 10%).
The study duration is anticipated to be approximately three years from the date the last patient rolls over from the HERCULES trial.
Dr Edwin Moses, CEO of Ablynx commented : "As pioneers in the treatment of acquired TTP, we are committed to making caplacizumab available for patients suffering from this severe disease for which there is currently no specifically approved drug available. The safety and efficacy of caplacizumab has been demonstrated in the Phase II study and recruitment in the recently expanded Phase III study is proceeding well ahead of schedule. We are on track to file for conditional approval of caplacizumab in early 2017 in Europe and to communicate Phase III topline results before the end of 2017. In parallel, we have started to invest in our own commercial infrastructure and key expertise to support the anticipated launch of caplacizumab in Europe and North-America."
Caplacizumab is a highly potent and selective bivalent anti-von Willebrand Factor (vWF) Nanobody® that received Orphan Drug Designation in the United States and Europe in 2009. Caplacizumab blocks the interaction of ultra-large vWF multimers (ULvWF) with platelets and, therefore, has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the microclots that cause the severe thrombocytopenia and organ and tissue damage in aTTP. This immediate effect protects the patient from the manifestations of the disease while the underlying disease process resolves.
The efficacy and safety of caplacizumab in conjunction with the standard of care (PEX) were evaluated in the Phase II TITAN study in 75 patients with aTTP. Caplacizumab was well-tolerated and the primary endpoint of reduction in time to platelet normalisation was met (p=0.005). Treatment with caplacizumab resulted in a nearly 40% reduction in time to platelet count normalisation as compared to placebo (i.e., a faster reversion of thrombocytopenia with consequent reduced use of PEX). Moreover, during treatment, caplacizumab reduced aTTP recurrences by 71% compared to placebo when administered as an adjunct to standard of care  . Post-hoc analyses of the Phase II TITAN study data 5 were performed to assess the impact of caplacizumab on a composite endpoint of major thromboembolic complications and aTTP-related mortality, as well as on refractoriness to standard treatment. The results demonstrate that a clinically meaningful lower proportion of subjects treated with caplacizumab experienced one or more major thromboembolic events, or died, as compared to placebo (11.4% versus 43.2%). In addition, fewer caplacizumab-treated patients, compared to those who received placebo, were refractory  to treatment (5.7% versus 21.6%; and 0% versus 10.8%, respectively depending on the definition of refractoriness 4 ). There were two deaths in the placebo group and both those patients were refractory to treatment; no deaths were reported in the caplacizumab group.
These Phase II results will serve as the basis for filing for conditional approval of caplacizumab in Europe in early 2017. The confirmatory Phase III HERCULES study is currently ongoing and will support the BLA filing in the United States. Results from this Phase III study are expected by the end of 2017.
Caplacizumab has the potential to be the first therapeutic specifically approved for the treatment of acquired TTP.
aTTP is an acute, ultra-rare, life-threatening, blood clotting disorder, affecting up to 11 per million people worldwide. It has a sudden onset caused by impaired activity of the ADAMTS13 enzyme (typically <10% of that in normal plasma), leaving ULvWF molecules uncleaved (vWF is an important protein involved in the blood clotting process). These ULvWF molecules spontaneously bind to blood platelets, resulting in severe thrombocytopenia (very low platelet count) and micro-clot formation in small blood vessels throughout the body 1 , leading to thrombotic complications and widespread organ damage 2 .
Up to 20% of patients die from an initial aTTP episode with most deaths occurring within 30 days of diagnosis 3 . In addition to the acute risks of the disease, patients experiencing an episode of aTTP may suffer long-term consequences such as cognitive deficits, depression, and arterial hypertension  , and are at risk for recurrence. The recurrence rate ranges from 10-84%  and typically occur within 1-2 years  , but recurrences have been reported up to 30 years after the initial episode  .
Ablynx is a biopharmaceutical company engaged in the development of Nanobodies® , proprietary therapeutic proteins based on single-domain antibody fragments, which combine the advantages of conventional antibody drugs with some of the features of small-molecule drugs. Ablynx is dedicated to creating new medicines which will make a real difference to society. Today, the Company has more than 45 proprietary and partnered programmes in development in various therapeutic areas including inflammation, haematology, immuno-oncology, oncology and respiratory disease. The Company has collaborations with multiple pharmaceutical companies including AbbVie, Boehringer Ingelheim, Eddingpharm, Genzyme, Merck & Co., Inc., Merck KGaA, Novartis, Novo Nordisk and Taisho Pharmaceuticals. The Company is headquartered in Ghent, Belgium. More information can be found on www.ablynx.com .
For more information, please contact
Dr Edwin Moses
t: +32 (0)9 262 00 07
m: +32 (0)473 39 50 68
Director IR & Corporate Communications
t: +32 (0)9 262 00 82
m: +32 (0)479 49 06 03
Follow us on Twitter @AblynxABLX
Ablynx media/analyst relations
Julia Phillips, Brett Pollard, Mo Noonan, Matthew Moss
t: +44 20 3727 1000
 Veyradier, NEJM 2016: "von Willebrand Factor - A new target for TTP treatment?"
 Scully et al , Br J Hem 2012; Sarode et al, J Clin Apher 2014; Chaturvedi et al, Am J Hem 2013
 Benhamou, Y. et al ., Haematologica 2012
 Defined as: 'failure of platelet response after 7 days despite daily plasma exchange treatment' or 'absence of platelet count doubling after 4 days of standard treatment, and LDH>upper limit of normal
 Peyvandi et al , notes to editor NEJM 2016
 Deford et al , Blood 2013
 Thejeel et al , American journal of hematology 2016
 Kremer Hovinga et al , Blood 2010
 Falter et al , Hamostaseologie 2013pdf format of the press release
Last updated on: 11/10/2016
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