Caplacizumab is a humanized, bivalent, variable domain-only immunoglobulin fragment that targets the A1 domain of von Willebrand factor in preventing abnormal microvascular thrombosis from occurring.1 Recently, the United States Food and Drug Administration (FDA) has granted approval of caplacizumab as the first therapy that explicitly treats acquired thrombotic thrombocytopenic purpura (aTTP) in adults.2 The approval was granted based on the efficacy results from the HERCULES study, which was also published in The New England Journal of Medicine.1
aTTP, also known as immune-mediated TTP, is a rare but fatal thrombotic microangiopathy that can produce symptoms such as severe thrombocytopenia and hemolytic anemia that occur at a rate of 3.7 cases per million people per year.3 An episode of TTP can lead to irreversible neurological deficits, acute renal failure, congestions in the heart and lungs, and premature death.1,3
Before caplacizumab was approved, the available treatment options for TTP was very limited and mainly consisted of daily plasma exchange and immunosuppressive therapy (e.g. glucocorticoids and rituximab).4 The new addition of TTP treatment options, caplacizumab, was previously tested in a phase 2 trial against placebo to demonstrate efficacy in terms of the time to normalization of platelet count, the incidence of TPP recurrence during treatment, the percentage of refractory diseases developed, and the incidence of major thromboembolic events.5-7
In the phase 3 double-blind, randomized, parallel group, multicenter placebo-controlled HERCULES trial, 145 adult patients diagnosed with TTP and previously received exactly one plasma exchange treatment were randomly assigned to receive caplacizumab (n=72) or placebo (n=73) on top of the standard plasma exchange and immunosuppressive therapy.1
The key findings in this study was that patients received caplacizumab had a significantly shorter time to platelet count normalization (2.69 days vs. 2.88 days in placebo arm; 95% CI: 1.89-2.83; p=0.01), and patients on the caplacizumab arm were 1.55 times (95% CI: 1.09-2.19) more likely to have a normalized platelet count than those in the placebo arm.1 The incidence of composite outcomes (including TTP-related death, recurrence of TTP, or major thromboembolic event during treatment period) was also significantly lower in the caplacizumab arm (12% vs. 49% in the placebo arm; p<0.001).1 The percentage of patients experienced a recurrence of TTP during the whole trial (treatment period and the follow-up period) was also significantly lower in the caplacizumab arm than the placebo arm (12% vs. 38%; p<0.001).1
The safety profile of caplacizumab was also examined, with gum or nose bleeding and headache being the most common adverse events that were associated with caplacizumab.1 In the prescribing information for caplacizumab approved by the FDA, there is a warning message about the risk of severe bleeding in patients with underlying coagulopathies.8 In light of this, the FDA advised healthcare providers to monitor patients closely for bleeding.2
As a side note, the caplacizumab approval application received the FDA’s Priority Review designation and Orphan Drug designation as an incentive to assist and encourage the development of drugs for rare diseases.2 This first step of advances in aTTP treatment has provided patients with a new treatment option that can reduce recurrences through inhibiting thrombi formation,1 and inspire future researchers to look for novel treatment targets in TTP.
1. Scully M, Cataland SR, Peyvandi F, et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346.
2. FDA approves first therapy for the treatment of adult patients with a rare blood clotting disorder. 2019. (Accessed March 8, 2019, at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm630851.htm.)
3. Rare Disease Database – Thrombotic Thrombocytopenic Purpura. (Accessed March 8, 2019, at https://rarediseases.org/rare-diseases/thrombotic-thrombocytopenic-purpura/.)
4. Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323-335.
5. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2016;374(6):511-522.
6. Peyvandi F, Callewaert F. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016;374(25):2497-2498.
7. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2017;15(7):1448-1452.
8. CABLIVI U.S. Prescribing Information, Ablynx N.V. Approved February 2019.