Ablynx [Euronext Brussels: ABLX; OTC: ABYLY] today announced that it has successfully completed patient recruitment in the multi-national, double-blind, placebo-controlled Phase III HERCULES study of caplacizumab, its first-in-class anti-von Willebrand factor (vWF) Nanobody® for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP), an ultra-rare, acute, life-threatening blood clotting disorder.
A total of 145 patients have been enrolled. Data from this Phase III study will be reported in the second half of 2017 and are expected to support the recently submitted Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) and a planned Biologics License Application (BLA) filing in the United States in 2018.
If approved by regulatory authorities, caplacizumab will be the first therapeutic specifically indicated for the treatment of aTTP.
Dr Robert K. Zeldin, Chief Medical Officer at Ablynx, commented:
"This is the largest randomised, double-blind, placebo-controlled study ever conducted in patients with aTTP. Recruiting 145 patients in just 20 months is an indication of the interest and enthusiasm of clinicians and their patients. Their commitment is enabling us to evaluate the role of caplacizumab in improving the current standard-of-care for this very severe disease. We thank everyone involved in this trial for their contribution and look forward to reporting the data later this year.
Caplacizumab is a highly potent and selective bivalent anti-vWF Nanobody that received Orphan Drug Designation in Europe and the United States 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, tissue ischemia and organ dysfunction in aTTP. This immediate effect of caplacizumab 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 of plasma exchange (PEX) and immunosuppression, were evaluated in the Phase II TITAN study in 75 patients with aTTP. Caplacizumab was well-tolerated and the primary endpoint was met (p=0.005), with caplacizumab treatment resulting in a 39% 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 recurrences of aTTP by 71% compared to placebo2. Post-hoc analyses of the Phase II TITAN study data 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%)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), . There were two deaths in the placebo group and both of those patients were refractory to treatment; no deaths were reported in the caplacizumab group.
The randomised, double-blind, placebo-controlled Phase III HERCULES study (NCT02553317) will evaluate the efficacy and safety of caplacizumab in patients with aTTP when administered in addition to the standard-of-care. The primary endpoint is time to platelet count normalisation, a measure of prevention of further microvascular thrombosis. Key secondary endpoints include a composite endpoint consisting of TTP-related mortality, recurrence of TTP and major thromboembolic events during study drug treatment, as well as the prevention of recurrence of TTP during the study period, refractoriness to treatment, and the effect on biomarkers of organ damage. Results from this Phase III study are expected in the second half of 2017.
A three-year follow-up study (NCT02878603) of patients who have participated in the HERCULES study is also in progress and will further evaluate the long-term safety and efficacy of caplacizumab and repeated use of caplacizumab, as well as characterizing the long-term impact of aTTP.
aTTP is an ultra-rare, acute, life-threatening, blood clotting disorder. It has a sudden onset caused by impaired activity of the ADAMTS13 enzyme, 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, leading to thrombotic complications and widespread organ damage.
Despite the current standard-of-care treatment of 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. The recurrence rate has been reported to range from 10-84% and recurrences typically occur within 1-2 years but have been reported up to 30 years after the initial episode, , . In addition, some patients are refractory to therapy3, 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.
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, 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.
 Peyvandi et al., notes to editor NEJM 2016
 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'
 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
 Thejeel et al., Am J Hem 2016
 Kremer Hovinga et al., Blood 2010
 Falter et al., Hämostaseologie 2013
 Deford et al., Blood 2013