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Highlights from

American Society of Hematology

Annual meeting 2018

San Diego 1-4 December 2018

TITAN and HERCULES: Caplacizumab - a new treatment option for patients with life-threatening aTTP?

Take-home messages
  • Mortality rates in patients with aTTP is currently 10-20%
  • Treatment with caplacizumab showed a statistically significant reduction in the time to platelet count response versus placebo
  • Caplacizumab was well tolerated and no new safety signals were identified
In the overall study period, there was an 84% reduction in the number of aTTP exacerbations with caplacizumab versus placebo (p<0.0001).

Caplacizumab combined with standard of care was effective and had a manageable safety profile in patients with acquired thrombotic thrombocytopenic purpura (aTTP), show results presented at the American Society of Hematology (ASH) 60th Annual Meeting 2018.

Although rare, aTTP is a life-threatening microangiopathy that can cause multiorgan ischaemia, through the accumulation of von Willebrand factor (vWF) multimers and subsequent platelet adhesion and microthrombus formation.

The current standard of care for patients with aTTP, which is a combination of immunosuppression via glucocorticoids and/or rituximab and daily plasma exchange (PE), previously improved survival from a near-fatal <10% to 80-90%.1

But a mortality rate of 10-20% is still too high, argued Professor Flora Peyvandi, Director of the Angelo Bianchi Bonomi Haemophilia and Thrombosis Centre, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Italy, who presented at ASH 2018. The current standard of care can also give rise to PE-related complications, unpredictable refractoriness to treatment and disease exacerbation when therapy is halted.

The team explored answers to this unmet need by observing the efficacy of caplacizumab, an anti-vWF humanised nanobody that prevents vWF-mediated formation of microthrombi in patients with aTTP.

Professor Peyvandi reported the results, which integrated data from two trials: TITAN (phase II, single-blind trial) and HERCULES (phase III, double-blind trial). Patients with aTTP and balanced baseline characteristics were randomised to either caplacizumab + PE and immunosuppression (n=108), or placebo + PE and immunosuppression (n=112), and were followed up 30 days after their last daily PE treatment. The trials were similarly designed; however, in HERCULES, switch to open label and treatment extension was allowed in specified circumstances.

The primary efficacy analysis, time to platelet count response, showed a statistically significant difference in favour of caplacizumab versus placebo, with a platelet normalisation rate ratio of 1.65 (95% CI: 1.24-2.20; p=0.0006).

Professor Peyvandi continued to report results from the secondary efficacy analysis, which found that caplacizumab provided a 72.6% reduction in aTTP-related death, recurrence of aTTP, or ≥1 treatment-emergent major thromboembolic event during the treatment period, compared with placebo (p<0.0001).

In the overall study period, there was an 84% reduction in the number of aTTP exacerbations with caplacizumab versus placebo (p<0.0001). Over one-fifth of patients in the TITAN trial relapsed after stopping treatment with caplacizumab, compared with 8% in the HERCULES trial, which the authors attributed to the enabling of treatment extension in patients with unresolved underlying immunological disease activity.

No patients receiving caplacizumab had refractory disease, compared with 8 patients (7.1%) in the placebo arm (p=0.0049). Mortality rate, which was examined after the end of treatment, was statistically significantly better for patients treated with caplacizumab; there were no deaths in this treatment arm versus 4 with placebo (3.6%; p=0.0477). The overall number of PE treatment days was reduced by 3.9 days with caplacizumab versus placebo.

The integrated safety data, which were also presented at ASH 2018, showed that the most common treatment-related adverse events were epistaxis and gingival bleeding, and no new safety signals were identified. The TITAN and HERCULES trial data confirm that caplacizumab is a well-tolerated and efficacious addition to standard of care for patients with aTTP.

Based on: Peyvandi F, Cataland S R et al. Integrated efficacy results from the phase II and phase III studies with caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (abstract 373). Presented on Sunday 2 December 2018.

Knoebl P, Scully M et al. Integrated safety results from the phase II and phase III studies with caplacizumab in patients with acquired thrombotic thrombocytopenic purpura (P3739). Presented on Monday 3 December 2018.

Reference:

  1. Kremer H, Coppo P et al. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers 2017; 17020(3):1-17

Top image: © Racksuz

Article image: © somersault18

The content and interpretation of these conference highlights are the views and comments of the speakers/authors.

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