The results of the phase II TITAN study with Caplacizumab for patients with acquired thrombotic thrombocytopenic purpura ( aTTP) have been published in The New England Journal of Medicine ( NEJM ).
Caplacizumab is a highly potent and selective bivalent anti-von Willebrand Factor ( vWF ) nanobody that received Orphan Drug Designation in the USA and EU in 2009.
Caplacizumab inhibits the interaction between ultra-large vWF and platelets by targeting the A1 domain of vWF. It thereby prevents platelet aggregation and the formation of micro-clots during the acute, critical phase of acquired TTP.
Caplacizumab’s clinical effect was demonstrated in the phase II TITAN, a single-blinded, randomised, placebo-controlled study.
In total, 75 patients were randomised on a 1:1 basis to active drug ( Caplacizumab ) or placebo, with all patients receiving the current standard of care.
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.
The TITAN study was conducted at 56 study centres worldwide.
For 6 patients who had undergone a plasma exchange prior to enrollment, the difference was even greater, with a median time to response of 2.4 days in the Caplacizumab arm and 4.3 days in the placebo group.
This has conferred a 39% reduction in the median time to response for those patients treated with Caplacizumab ( event rate ratio, ERR= 2.2 ).
A post-hoc analysis of 58 patients with baseline ADAMTS13 activity below 10% indicated the median time to response was 3 days with Caplacizumab and 4.6 days with placebo ( ERR= 1.63 ).
Three patients in the Caplacizumab group had an exacerbation compared with 11 patients in the placebo arm.
Relapse occurred in 8 patients in the Caplacizumab group within 1 month of stopping the drug. Seven of those patients had ADAMTS13 activity that remained below 10%.
Acquired thrombotic thrombocytopenic purpura is an ultra-rare, acute, auto-immune 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 less than 10% of that in normal plasma ), leaving ultra-large vWF molecules un-cleaved. These ULvWF molecules spontaneously bind to blood platelets, resulting in severe thrombocytopenia and micro-clot formation in small blood vessels throughout the body.
aTTP is associated with major morbidities in the brain ( e.g. stroke ), heart and kidney and impacts life expectancy and quality of life.
Mortality is high at 10-20%, typically occurring within 2 weeks after initial diagnosis.
Moreover, about 36% of patients have recurrences after treatment with the current standard of care, which consists of daily PEX [ Therapeutic Plasma Exchange ] and immune-suppressants, and these recurrences have the potential to cause further organ damage and poorer longer term outcomes. ( Xagena )
Source: Ablynx, 2016