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Caplacizumab induces clinically meaningful improvements in patients with acquired thrombotic thrombocytopenic purpura

Caplacizumab is a bivalent nanobody that targets the A1 domain of von Willebrand factor (vWF). Results of the phase III HERCULES trial demonstrated that patients with acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) randomised to receive caplacizumab were 1.55 times more likely than those in the placebo group to achieve platelet count normalization (p< 0.01). Furthermore, those receiving caplacizumab showed a 74% lower risk of TTP-related death, recurrence, or a major thromboembolic event (such as stroke) while undergoing treatment (p< 0.0001). Patients treated with caplacizumab also saw a significant reduction in the number of days they required PE (38%), in the time spent in the intensive care unit (65%), and in the overall time spent in the hospital (31%). Caplacizumab was found to have a favourable safety profile, with muco-cutaneous bleedings as the most frequently reported adverse event.

Backgrounder on aTTP

Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic haemolytic anaemia, and organ ischemia. The underlying cause of aTTP is the development of inhibitory autoantibodies directed against ADAMTS13, an enzyme that is responsible for the cleavage of vWF. As a result of these antibodies, patients with aTTP have severe vWF deficiency, which leads to intravascular vWF-platelet aggregation and microvascular thrombosis. If aTTP is left untreated, about 90% of patients will die within 30 days of the acute presentation, when the platelet count is at its lowest and the condition is most active. The standard treatment consists of plasma exchange (PE) and immunosuppression therapy to remove the antibody-producing cells. While this regimen is effective in clearing the harmful antibodies and replenishing the missing ADAMTS-13 enzyme, it can take over 10 days for a patient to realize the treatment’s full effect. During this period he or she can die from a stroke or other complication while waiting for the antibodies to clear. Caplacizumab is a novel bivalent nanobody that targets the A1 domain of vWF. As a result this agent, developed by the Belgian biotech company Ablynx, inhibits the interaction between ultra-large vWF with platelets and has an immediate effect on platelet aggregation and the ensuing formation and accumulation of the micro-clots that cause the severe thrombocytopenia, tissue ischemia and organ dysfunction in aTTP.

Outcomes of HERCULES  trial presented during ASH2017

In the HERCULES trial, 145 patients with an acute episode of aTTP who had received one PE treatment were randomised (1:1) to placebo or caplacizumab, in addition to daily PE and corticosteroids. A single IV dose (10mg) of study drug was given before the first on-study PE and a SC dose (10mg) was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of on-going disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients were monitored for safety for at least 28 days after their treatment ended. The primary endpoint of the study was the time to platelet count response, defined as a platelet count ≥ 150×109/L with stop of daily PE within 5 days.

In addition to this the trial had 4 key secondary endpoints:

  • The 1st was a composite of aTTP-related death, aTTP recurrence, or major thromboembolic event during the study drug treatment period;
  • The 2nd looked at recurrences during the entire study period;
  • The 3rd secondary endpoint evaluated refractoriness to therapy, defined as an absence of platelet count doubling after 4 days of treatment and LDH still above normal;
  • The 4th study objective was the time to normalization of 3 organ damage markers: LDH, cardiac troponin I and serum creatinine.

Patients randomised to receive caplacizumab were 1.55 times more likely than those in the placebo group to achieve platelet count normalization (p< 0.01). Furthermore, those receiving caplacizumab showed a 74% lower risk of TTP-related death, recurrence, or a major thromboembolic event (such as stroke) while undergoing treatment (p< 0.0001). During the overall study period, 28 patients in the placebo group experienced a recurrence versus 9 patients in the caplacizumab group, representing a 67% reduction in the risk of recurrence (p< 0.001). In all 6 caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still <10% at the stop of study drug, reflecting on-going disease.

Greater responsiveness to treatment and less time spent overall in the hospital

Patients receiving caplacizumab also showed greater responsiveness to treatment, a trend for a faster normalization of organ damage markers compared to the placebo group, and only minor side effects, such as nosebleeds, bleeding of the gums, and bruising. Patients treated with caplacizumab also saw a significant reduction in the number of days they required PE (38%), in the time spent in the intensive care unit (65%), and in the overall time spent in the hospital (31%). These reductions suggest that the drug could also have significant financial benefits when used in the treatment of aTTP.

Adverse events profile

In the caplacizumab group, the most common treatment related emergent adverse events (TEAEs) were epistaxis, gingival bleeding, and bruising. TEAEs led to treatment discontinuation in 12.3% of placebo patients as compared to 7% in the caplacizumab arm. During the study drug treatment period, 3 patients on placebo died. One caplacizumab-treated patient died during the follow up period, but this death was considered to be unrelated to the treatment.

In summary, the results of HERCULES show that caplacizumab is a treatment that offers protection during the most acute, risky period of this disease and bridges the time one has to wait for the inhibitory autoantibody levels to be cleared via PE. The therapy is beneficial for patient outcomes and potentially offers pharmaco-economical benefits and as such can be an important addition to the therapeutic armamentarium for clinicians and the hospital in the near future.

Reference

Scully M, Cataland S, Peyvandi F, et al. Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura. Presented at ASH 2017; Abstract LBA-1.

Speaker Marie Scully

Scully

Prof.dr. Marie Scully, Univermmsity College Hospital London, United Kingdom

 

See: Keyslides

 

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