- Caplacizumab is a potential first-in-class therapeutic with Orphan Drug status
- Caplacizumab, in addition to plasma exchange and immunosuppressive therapy, has the potential to become an important new treatment for acquired thrombotic thrombocytopenic purpura (TTP)
- Additional data suggest that caplacizumab prevents consumption of platelets, thereby protecting patients from further formation of microvascular thrombi
- Strong Phase II clinical proof-of-concept data published in June 2014
Additional Phase II results will be discussed during a webcast on Thursday 11 December at 15h CET, 9 am EST
The webcast may be accessed on the home page of Ablynx's website at www.ablynx.com or by clicking here
To participate in the Q&A, dial +32(0)2 402 30 92 with confirmation code 7878101
Ghent/Zwijnaarde, Belgium, Dec. 8, 2014 (GLOBE NEWSWIRE) -- Ablynx [Euronext Brussels: ABLX] today announced additional clinical results, including some post hoc analyses, from the worldwide Phase II TITAN trial with its anti-von Willebrand Factor (vWF) Nanobody®, caplacizumab, in patients with acquired thrombotic thrombocytopenic purpura (TTP). The results were presented today (abstract #229) by Professor Peyvandi, Principal Investigator for the TITAN trial, at the American Society of Hematology (ASH) Annual Meeting in San Francisco, CA.
TTP is a rare disorder of the blood coagulation system that causes formation of microthrombi that block the small blood vessels leading to tissue ischemia.
The results of the Phase II study suggest the potential protective effect of caplacizumab against microvascular thrombosis and related tissue ischemia during the acute phase of a TTP episode and further demonstrate that caplacizumab is generally well tolerated, with an increase in mild bleeding events which were readily managed and did not require vWF or Factor VIII substitution.
The majority of patients had very low platelet counts at the start of the study, had experienced their first TTP episode and had ADAMTS13 activity below 10% (a measure of the underlying disease activity). All patients received the standard of care for treating acquired TTP, i.e. daily plasma exchange (PE), and the majority of patients also received immunosuppressive therapy (corticosteroids).
Only 8% (n=3) of caplacizumab treated patients experienced an exacerbation while on treatment as compared to 28% (n=11) of patients on placebo. It is however important to note that 22% (n=8) of caplacizumab patients experienced a relapse event in the first month after stopping caplacizumab treatment, with all but one of those patients having ADAMTS13 activity below 10% around the time when drug treatment was stopped. This suggests that, in order to maintain the Nanobody's protective effect, some patients may require longer treatment with caplacizumab until their underlying disease is resolved.
Exploratory analysis of biomarkers of tissue damage in these TTP patients illustrated the detrimental consequences of microvascular thrombosis in TTP, with 49% of all patients at the start of the study having an above normal value of Troponin I or T, markers of cardiac injury. Similar observations have been reported in the literature. Importantly, in patients who were treated with caplacizumab, these biomarkers returned more rapidly to the normal range, suggesting that the inhibition of microthrombi formation by caplacizumab may result in reduced cardiac injury.
Commenting on the full analysis of the worldwide Phase II TITAN trial with caplacizumab, Professor Flora Peyvandi, Principal Investigator, at IRCCS Maggiore Hospital, University of Milan, Italy said:
"The detailed findings of this study confirms our conviction that caplacizumab has the potential to become an important tool in the management of acquired TTP. The results show that caplacizumab is able to control the acute phase of the disease and buys time for the later onset of the immunosuppressive treatment which is often needed to fully resolve a TTP episode."
Dr Dominique Tersago, Chief Medical Officer of Ablynx, added:
"These results strengthen our belief in caplacizumab's mechanism of action as a potential novel treatment for acquired TTP. We will now work diligently to ensure that this product could become available to patients at the earliest opportunity."
Caplacizumab is a bivalent anti-vWF Nanobody which is highly potent and selective. It received Orphan Drug Designation in the US and EU in 2009 and could be the first drug specifically approved for the treatment of acquired TTP as an adjunct to plasma exchange.
Von Willebrand factor (vWF) is a blood glycoprotein involved in haemostasis, a complex process that causes the bleeding process to stop. vWF's primary function is to bind to other proteins, including glycoprotein Ib in the initiation of platelet adhesion.
vWF is implicated in TTP where ultra-large, multimeric precursors of vWF (UL-vWF) are present in the blood of patients leading to the formation of unwanted characteristic string-like clots in small blood vessels. In healthy subjects, UL-vWF are immediately cleaved into smaller, regular-sized multimers by the ADAMTS13 enzyme. In patients with TTP, activity of the ADAMTS13 enzyme is impaired (<10%) due to the formation of auto-antibodies against the enzyme. In some cases, ADAMTS13 activity is normal (>10%) but UL-vWF are present as a result of massive endothelial stimulation with consequent release of UL-vWF multimers in amounts exceeding the system's ability to degrade them.
Caplacizumab inhibits platelet binding to UL-vWF and thus has the potential to prevent the formation of these string-like clots in the blood of patients with acquired TTP. Importantly, caplacizumab selectively prevents thrombus formation in high-shear blood vessels and is expected not to interact with haemostasis in normal, healthy blood vessels.
About Phase II TITAN trial
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 protocol for the study was adapted in September 2013, to also allow one day of plasma exchange prior to study enrolment. Those patients in the active drug treatment arm immediately received an intravenous bolus dose of 10 mg caplacizumab and then a 10 mg subcutaneous dose of the drug daily until 30 days had elapsed after the final plasma exchange. Patients in the control arm received placebo at the same time points.
TTP is a rare disorder of the blood coagulation system that causes extensive microscopic thromboses in small blood vessels throughout the body. It is a potentially life-threatening disorder characterised by thrombocytopenia, haemolytic anaemia and microvascular thrombosis causing variable degrees of tissue ischemia and infarction. TTP exists in two forms: a congenital and an acquired form, with the latter accounting for >90% of the patients. There are currently no drugs specifically approved for the treatment of TTP. The standard of care for the acquired form of TTP is multiple daily plasma exchanges (PE) until confirmed platelet normalisation which occurs when the patient's platelet count returns to normal, as well as immunosuppressant treatment. Daily PE requires lengthy hospital stays and may be associated with clinical complications. Additionally, a significant number of patients will subsequently suffer a relapse after recovering from a first TTP episode. There are believed to be approximately 10,000 TTP-related events in the US and top 15 European markets per year.
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 30 proprietary and partnered programmes in development in therapeutic areas including inflammation, haematology, oncology and respiratory disease. The Company has collaborations and significant partnerships with pharmaceutical companies including AbbVie, Boehringer Ingelheim, Merck & Co, Merck Serono and Novartis. The Company is headquartered in Ghent, Belgium. More information can be found on www.ablynx.com.
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 In healthy subjects, ultra-large, multimeric precursors of vWF (UL-vWF) are immediately cleaved into smaller, regular-sized multimers by the ADAMTS13 enzyme. But in the majority of patients with acquired TTP, activity of this ADAMTS13 enzyme is impaired (activity <10%) due to the formation of auto-antibodies against the enzyme.
 Journal of Thrombosis and Haemostasis, Hughes et al, 2009
pdf format of the press release http://hugin.info/137912/R/1878224/662002.pdf