Ablynx [Euronext Brussels: ABLX; OTC: ABYLY] today announced that the first Japanese healthy volunteers have been dosed in the Phase I single centre, randomised, double-blind, placebo-controlled study of caplacizumab, its first-in-class anti-von Willebrand factor (vWF) Nanobody® being developed for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP).
The goal of this Phase I study is to assess the safety, tolerability, PK and PD profiles and immunogenicity of caplacizumab in healthy Japanese subjects, before initiating studies in Japanese patients with aTTP. The study consists of single ascending dose and multiple dose parts with blinded safety reviews prior to proceeding to a higher dose or multiple dosing (NCT03172208). In total, 60 healthy Japanese and Caucasian subjects will be enrolled into the trial.
Dr Robert K. Zeldin, Chief Medical Officer at Ablynx, commented:
"The start of this Phase I study is an important step in making caplacizumab available to Japanese patients suffering from aTTP. The study results are expected to provide insights on the safety and dosing of caplacizumab in Japanese subjects and enable bridging of data between Japanese and Caucasian populations. We are looking forward to reporting the results of this study before the end of 2017. This year, we will also report the top line results from our Phase III HERCULES study in 145 patients with acquired TTP."
Caplacizumab is a 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 has the potential to protect 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 placebo. 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%)2, . 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 and these results are expected to support a BLA filing in the United States in 2018. A Marketing Authorisation Application (MAA) has already been submitted to the European Medicines Agency (EMA) for approval of caplacizumab in aTTP. If approved by regulatory authorities, caplacizumab will be the first therapeutic specifically indicated for the treatment of aTTP.
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 a 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, myocardial infarction) and of recurrence of disease. Some patients are refractory to therapy3, which is associated with a 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., Kenilworth, New Jersey, USA; Merck KGaA; Novartis; Novo Nordisk and Taisho Pharmaceuticals. The Company is headquartered in Ghent, Belgium. More information can be found on www.ablynx.com.