Clinical Trials

Date: 2016-05-26

Type of information: Presentation of results at a congress

phase: 2

Announcement: presentation of results at the 21st Congress of the European Hematology Association (EHA), being held from 9-12 June 2016 in Copenhagen

Company: Ablynx (Belgium)

Product: caplacizumab

Action mechanism:

• nanobody. Caplacizumab is a bivalent anti-von Willebrand Factor (vWF) Nanobody. vWF is implicated in thrombotic thrombocytopenic purpura (TTP), a rare disease where pre-cursors of vWF (ultra-large vWF multimers; UL-vWF) are present in the blood of patients and lead to blood clot formation and potentially life-threatening pathology. 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.
• Caplacizumab 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.

     

Disease: thrombotic thrombocytopenic purpura

Therapeutic area: Autoimmune diseases - Rare diseases

Country: Australia, Austria, Belgium, Bulgaria, France, Germany, Israel, Italy, Romania, Spain, Switzerland, UK, USA

Trial details:

• 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. The first centres opened in September 2010 and the protocol of the study was adapted in September 2013 to facilitate recruitment. In January 2014, Ablynx announced that some improvement in recruitment had been seen since amending the clinical protocol, nevertheless, Ablynx decided to stop recruitment of the trial to allow earlier analysis of the data for potential proof-of-concept.
• 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. The primary endpoint of the trial was the time to confirmed platelet normalisation which guides the clinical decision to stop the daily plasma exchanges. (NCT01151423)

Latest news:

• • On May 26, 2016, Ablynx announced that a posthoc analysis of the worldwide Phase II TITAN study of caplacizumab, in patients with acquired thrombotic thrombocytopenic purpura (aTTP), will be presented at the 21st Congress of the European Hematology Association (EHA). It has been previously reported that the efficacy and safety of caplacizumab in conjunction with the standard of care (plasma exchange) were evaluated in a Phase II study in 75 patients with aTTP. Caplacizumab was well tolerated and the primary endpoint of a reduction in time to platelet normalisation was achieved with statistical significance (p= 0.005). In addition, during treatment, caplacizumab reduced aTTP recurrences by 71% compared to placebo when administered as an adjunct to standard of care. Despite the current standard of care, mortality from an episode of acquired TTP is still reported to be up to 20% and patients remain at risk of life-threatening thrombotic complications. A post-hoc analysis of the Phase II data was performed to assess the impact of caplacizumab on a composite endpoint of major thromboembolic events and TTP-related mortality. The results demonstrate that a significantly 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%, nominal p-value of 0.006). These clinically meaningful results suggest that treatment with caplacizumab has the potential to reduce the major morbidity and mortality associated with acquired TTP. The results from this post-hoc analysis will be presented during a poster presentation on 10 June 2016 (Abstract LB418  - “Impact of caplacizumab treatment on mortality and major thromboembolic events in acquired TTP: Phase II TITAN study results”).
• • On February 11, 2016, Ablynx announced that 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). The NEJM paper, titled "Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura" (Peyvandi et al., NEJM 2016: published 11 February 2016), reported data from the worldwide Phase II TITAN clinical trial which was a single-blinded, randomised, placebo-controlled study. In total, 75 patients were randomised on a 1:1 basis to active drug or placebo, with all patients receiving the current standard of care. 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. The TITAN study was conducted at 56 study centres worldwide, with investigators from countries including Italy, England, Switzerland, the USA and Austria. Caplacizumab's clinical effect was demonstrated in the Phase II TITAN study in 75 patients with aTTP: As indicated by a nearly 40% reduction in median time to platelet count normalisation (p = 0.005). Treatment with caplacizumab reduced the use of daily plasma exchange (PEX) and prevented further consumption of platelets in microthrombi and small blood vessel occlusion. As shown by the low number of recurrences requiring re-initiation of daily plasma exchange during treatment with caplacizumab (N=3) vs. placebo (N=11). These results will serve as the basis for filing for conditional approval in Europe in H1 2017.
• A  worldwide Phase III study is also ongoing. The Hercules study is a multinational, double-blind, placebo-controlled study evaluating the efficacy and safety of caplacizumab, in conjunction with the standard of care, in patients with aTTP. The study is expected to enrol 92 patients at clinical sites across 17 countries. The primary endpoint is time to platelet count normalisation. Other clinically relevant endpoints include: the prevention of recurrence of the presenting TTP episode after stopping daily PEX; the effect on biomarkers of organ damage; severe morbidity associated with tissue ischemia and; mortality. Recruitment for this study is expected to be completed by the end of 2017, followed by an anticipated BLA filing in the USA in 2018.
• • On June 17, 2015, Ablynx announced that additional data from the post-hoc analysis of the worldwide Phase II TITAN study with its wholly-owned anti-von Willebrand Factor (vWF) Nanobody®, caplacizumab, in patients with acquired thrombotic thrombocytopenic purpura (TTP), will be presented at the 2015 Annual Meeting of the International Society on Thrombosis and Haemostasis (ISTH), being held from 20-25 June 2015 in Toronto, Canada . The efficacy and safety of caplacizumab in conjunction with the standard of care were evaluated in the TITAN study and the primary endpoint of a reduction in time to platelet normalization was achieved. Additional post-hoc analyses were performed on plasma exchange (PE) parameters and biomarkers of organ damage.
• Abstract LB006: "Additional data from the TITAN trial with the anti-vWF Nanobody, caplacizumab, in the treatment of acquired TTP"  In the majority of patients with acquired TTP, the activity of the ADAMTS13 enzyme is impaired due to the formation of auto-antibodies against the enzyme. The potential of ADAMTS13 levels as a predictive marker of underlying disease activity and subsequent exacerbations and relapses was evaluated, using data from the TITAN study. Abstract OR363: "The predictive value of ADAMTS13 activity for treatment monitoring of patients with acquired TTP; data from the Phase II TITAN trial with caplacizumab". The key take-aways from the Phase II TITAN study with caplacizumab will also be presented during the session 'Highlights of ISTH' on 25 June 2015 at 12:00am ETD (18:00h CET) which provides a synopsis of the top thrombosis and haemostasis research presented at the congress. Shortly after the conference, both oral presentations will be made available on the Ablynx website under the R&D portfolio section. Ablynx expects to start the Phase III registration study for caplacizumab in Europe, the US and Canada, in H2 2015. In parallel, the Company will make further preparations to file for conditional approval for caplacizumab in Europe in 2017. At the same time, Ablynx is exploring the optimal value-creating commercial strategy for this asset and expects to announce its conclusions later this year.
• • On June 17, 2014, Ablynx announced that it has achieved positive results in the Phase II TITAN study with the anti-vWF Nanobody®, caplacizumab, in patients with acquired thrombotic thrombocytopenic purpura (TTP), a rare disorder of the blood coagulation system that causes microthrombi to form which can block small blood vessels throughout the body. Treatment with caplacizumab plus standard of care resulted in a statistically significant reduction in time to confirmed normalisation and was associated with fewer exacerbations and more complete remissions as compared to patients receiving the standard of care plus placebo. The results from this study showed that the group of patients treated with caplacizumab, in conjunction with plasma exchange, achieved confirmed platelet normalisation at more than twice the rate of the group receiving the standard of care plus placebo at any time during the 30-day period after start of study drug, as demonstrated by the hazard ratio of 2.2 (p = 0.013, 95% confidence interval [1.28-3.78]); where the "hazard" is the rate at which an event occurs, with the event here being confirmed platelet normalisation. Time to confirmed platelet normalisation for patients who had not received a plasma exchange prior to initial dosing with caplacizumab was a median of 3.0 days in the caplacizumab arm compared to a median of 4.9 days in the placebo arm - a potentially clinically meaningful 39% decrease.
• The potential protective effect of caplacizumab in the treatment of TTP was also shown by the 73% fewer patients who experienced an exacerbation in the active treatment arm compared to the control group, with 3 (8%) of patients treated with caplacizumab experiencing an exacerbation compared to 11 (28%) treated with placebo. An exacerbation is defined as the recurrence of thrombocytopenia (low platelet count) requiring re-initiation of plasma exchange treatment within 30 days after stopping the initial daily plasma exchanges. Importantly, 81% of caplacizumab treated patients achieved complete remission compared to 46% of placebo treated patients, where "complete remission" is defined as confirmed platelet normalisation together with an absence of exacerbations. TTP is a serious and potentially life-threatening disease. There were two deaths in the trial, both in the placebo arm. The number of patients with a treatment-emergent serious adverse event was similar across both treatment arms, with 20 (57%) patients in the caplacizumab arm compared to 19 (51%) patients in the placebo arm. The number of treatment-emergent adverse events was also similar across both arms of the study. Study treatment was stopped due to a treatment-emergent adverse event in four patients treated with caplacizumab and in two patients treated with placebo. An increased bleeding tendency was observed for caplacizumab compared to placebo, with 66 events compared to 35 respectively (11% and 6% of all reported treatment-emergent adverse events per treatment arm respectively). Of these treatment-emergent adverse events, five were serious adverse events in two subjects treated with caplacizumab compared to two serious adverse events in two subjects on placebo. Based on the top-line data at this time, caplacizumab can be considered to be generally well tolerated compared to placebo, with a manageable increase in bleeding tendency. Further analyses of the study results are still ongoing and the company now plans to start a Phase III trial in 2015.

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