Clinical Trials

Date: 2017-12-12

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the 59th American Society of Hematology (ASH) Annual Meeting in Orlando

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.
• The product 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.
• In February 2017, based on the Phase II TITAN study results, a Marketing Authorisation Application (MAA) was submitted to the European Medicines Agency (EMA) for approval of caplacizumab in aTTP. In July 2017, Ablynx received Fast Track designation from the FDA for caplacizumab for the treatment of aTTP.
• Results from the Phase III HERCULES study are expected to further support the MAA, as well as a planned Biologics License Application (BLA) filing in the United States in 2018. If approved by regulatory authorities, caplacizumab would be the first therapeutic specifically indicated for the treatment of aTTP.

Disease: thrombotic thrombocytopenic purpura (TTP)

Therapeutic area: Autoimmune diseases - Rare diseases

Country: Australia, Austria, Belgium, Canada, Czech Republic, France, Hungary, Israel, Italy, The Netherlands, Spain, Switzerland, Turkey, UK, USA

Trial details:

• The HERCULES study is a phase III, double blind, placebo-controlled, randomized study to evaluate the efficacy and safety of caplacizumab treatment in more rapidly curtailing ongoing microvascular thrombosis when administered in addition to standard of care treatment in subjects with an acute episode of acquired thrombotic thrombocytopenic purpura (aTTP). The study recruited 145 patients. Patients with an acute episode of aTTP were randomised 1:1 to receive either caplacizumab or placebo in addition to standard-of-care treatment (i.e. daily plasma exchange [PEX] and immunosuppression). Patients received a single intravenous bolus of 10mg caplacizumab or placebo followed by daily subcutaneous dose of 10mg caplacizumab or placebo until 30 days after the last daily PEX. If, at the end of this treatment period, there was evidence of persistent underlying disease activity indicative of an imminent risk for recurrence, the treatment could be extended for additional seven-day periods up to a maximum of 28 days. Patients were followed up for a further 28 days after discontinuation of treatment.
• (NCT02553317)
• A three-year follow-up study of patients who have completed the HERCULES study is in progress and will further evaluate the long-term safety and efficacy of caplacizumab and repeated use of caplacizumab, as well as characterising the long-term impact of aTTP (NCT02878603).

Latest news:

• • On December 12, 2017, Ablynx  announced  presentation of additional results from the Phase III HERCULES study with caplacizumab at the 59th Annual Meeting of the American Society of Hematology (ASH). These new data relate to additional pre-specified secondary endpoints and demonstrate that treatment with caplacizumab resulted in a clinically meaningful reduction in the use of PEX and length of stay in the ICU and the hospital.
• The number of days of PEX during the overall treatment period was 38% lower in the caplacizumab group compared to the placebo arm (5.8 days versus 9.4 days) resulting in a 41% reduction in the volume of plasma used (21.3L on caplacizumab compared to 35.9L in the placebo group). For those patients admitted to the ICU, the number of days in intensive care was reduced by 65% for patients treated with caplacizumab compared to placebo (3.4 days versus 9.7 days, respectively). The overall duration of hospitalisation in the caplacizumab group was reduced by 31% compared to the placebo group (9.9 days versus 14.4 days, respectively).
• • On October 2, 2017, Ablynx announced topline results from the Phase III HERCULES study with caplacizumab for the treatment of acquired thrombotic thrombocytopenic purpura. Treatment with caplacizumab in addition to standard-of-care resulted in a statistically significant reduction in time to platelet count response, the primary endpoint of the study and a measure of prevention of further microvascular thrombosis. Patients on caplacizumab were 1.5 times more likely to achieve platelet count response at any given time point, compared to patients treated with placebo.
• The study also met the first two key secondary endpoints. Treatment with caplacizumab resulted in a 74% reduction in the percentage of patients with acquired thrombotic thrombocytopenic purpura-related death, recurrence of acquired thrombotic thrombocytopenic purpura, or at least one major thromboembolic event during study drug treatment, with recurrences being the driver for achievement of this endpoint. In addition, the proportion of patients with a recurrence of acquired thrombotic thrombocytopenic purpura in the overall study period (including the 28 day follow-up after discontinuation of study drug treatment) was 67% lower in the caplacizumab arm compared to the placebo arm, demonstrating the durability of the treatment effect.
• Analysis of the third key secondary endpoint showed that no patients treated with caplacizumab were refractory to treatment compared to three patients treated with placebo. The analysis of the fourth key secondary endpoint showed a trend to faster normalisation of the organ damage markers (lactate dehydrogenase, cardiac troponin I and serum creatinine) in patients treated with caplacizumab.
• Based on the topline data, the safety profile of caplacizumab is consistent with its mechanism of action and the Phase II TITAN study results. The number and nature of treatment-emergent adverse events (TEAEs) were similar between the treatment groups. Serious TEAEs were more common in the placebo group, driven by the percentage of patients experiencing a recurrence of acquired thrombotic thrombocytopenic purpura. Consistent with the mechanism of action of caplacizumab, the percentage of subjects with any bleeding-related TEAE was higher in the caplacizumab treatment group than in the placebo treatment group (66.2% vs. 49.3%). Most bleeding-related TEAEs were mild or moderate in severity. There were three deaths in the placebo group and none in the caplacizumab group during the study drug treatment period. One patient in the caplacizumab group died in the follow-up period after completing the study drug treatment and this was assessed by the investigator not to be related to study drug.
• • On May 2, 2017, Ablynx announced that it has successfully completed patient recruitment in the multi-national, double-blind, placebo-controlled Phase III HERCULES study of caplacizumab 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.
• The efficacy and safety of caplacizumab in conjunction with the standard of care of plasma exchange 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
• • On October 10, 2016, Ablynx announced that the first patient with acquired thrombotic thrombocytopenic purpura, who completed the Phase III HERCULES study of caplacizumab, has rolled-over into a three-year follow-up study. The objectives of this study are to evaluate the long-term safety and efficacy of caplacizumab and repeated use of caplacizumab, and to characterise the long term impact of aTTP. Patients will attend twice yearly visits and undergo a number of clinical, cognitive, and quality of life assessments. Safety laboratory parameters, immunogenicity of repeated treatment with caplacizumab and disease-related markers will be evaluated.
• Upon any recurrence of acquired TTP, standard-of-care treatment consisting of daily plasma exchange (PEX) and immunosuppression will be initiated together with open-label caplacizumab. Patients will receive an intravenous bolus injection of caplacizumab at the start of PEX treatment followed by daily subcutaneous injections for the duration of daily PEX and for 30 days thereafter. Treatment with caplacizumab may be extended in the case of persistent signs and symptoms of underlying disease (e.g. ADAMTS13 activity profile remains below 10%).
• The study duration is anticipated to be approximately three years from the date the last patient rolls over from the HERCULES trial. The efficacy and safety of caplacizumab in conjunction with the standard of care (PEX) were evaluated in the Phase II TITAN study in 75 patients with aTTP. Caplacizumab was well-tolerated and the primary endpoint of reduction in time to platelet normalisation was met (p=0.005). Treatment with caplacizumab resulted in a nearly 40% reduction in time to platelet count normalisation as compared to placebo (i.e., a faster reversion of thrombocytopenia with consequent reduced use of PEX). During treatment, caplacizumab reduced aTTP recurrences by 71% compared to placebo when administered as an adjunct to standard of care. Post-hoc analyses of the Phase II TITAN study data5 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%). 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 refractoriness4). There were two deaths in the placebo group and both those patients were refractory to treatment; no deaths were reported in the caplacizumab group. These phase II results will serve as the basis for filing for conditional approval of caplacizumab in Europe in early 2017. The confirmatory Phase III HERCULES study is currently ongoing and will support the BLA filing in the United States. Results from this Phase III study are expected by the end of 2017. The belgian biotech is also investing in its own commercial infrastructure to support the anticipated launch of caplacizumab in Europe and North-America.
• • On September 29, 2015, Ablynx announced the initiation of a multinational, double-blind placebo-controlled Phase III "HERCULES" study evaluating efficacy and safety of caplacizumab, its wholly-owned anti-vWF Nanobody, in acquired thrombotic thrombocytopenic purpura. The study is expected to enrol 92 patients at clinical sites across 17 countries. The Phase III "HERCULES" study will evaluate the efficacy and safety of caplacizumab in patients with acquired TTP 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. Other clinically relevant endpoints include the prevention of recurrence of the presenting TTP episode after stopping daily PE, the effect on biomarkers of organ damage, severe morbidity associated with ischemia, and the mortality rate.

Is general: Yes