HERCULES

Background

Phase 3, multicenter, double-blind, placebo-controlled RCT (HERCULES). 145 patients with acquired thrombotic thrombocytopenic purpura (aTTP, immune-mediated TTP), confirmed by ADAMTS13 activity <10% or clinical suspicion pending confirmation. Patients received therapeutic plasma exchange (TPE) and immunosuppression; caplacizumab was added as an anti-vWF nanobody (bivalent single-domain antibody) targeting the A1 domain of von Willebrand factor to block platelet–vWF interaction. The prior phase 2 TITAN trial had shown proof-of-concept; HERCULES was designed to confirm efficacy and safety.

Interventions and follow up

Arm A: Caplacizumab 10 mg IV bolus before first TPE, then 10 mg SC daily during TPE + 30 days after last TPE (total up to ~90 days)
Arm B: Placebo IV/SC on same schedule; all patients received TPE + corticosteroids ± rituximab per institutional practice
Primary endpoint: Time to platelet count response (platelet ≥150×10⁹/L and cessation of TPE)
mFollow up: 3 months (treatment phase) + 28-day follow-u

Results

Time to platelet response: 2.69 vs 2.88 days (ratio 1.55, 95% CI 1.10–2.20), P=.01
Composite outcome (TTP-related death, recurrence, or ≥1 thromboembolic event): 12% vs 49%, P<.001
TTP recurrence during study: 12% vs 38%, P<.001
Refractory TTP: 0% vs 3%
TTP-related death: 0% vs 3%
Number of TPE sessions: Median 5 vs 7, P<.001

Adverse events

Main adverse events: Mucocutaneous bleeding (any grade): 65% vs 48% — predominantly mild epistaxis, gingival bleeding, and skin bruising. Serious bleeding: 11% vs 4%. No intracranial hemorrhage. No antibodies against caplacizumab detected. Headache, fatigue, and pyrexia were common in both arms. Thrombotic events still occurred in 12% of placebo arm vs fewer in caplacizumab arm. Upon study drug discontinuation, ADAMTS13 activity-driven TTP recurrence risk was the main clinical concern.

Conclusions

Caplacizumab significantly reduced TTP recurrence and thromboembolic events and shortened time to platelet response in aTTP, establishing it as the first targeted therapy approved for this condition when added to standard plasma exchange and immunosuppression.

Key Limitations

Key Limitations: ADAMTS13 confirmation was not required at enrollment — ~10% of patients had ADAMTS13 activity >10% at baseline (did not have true aTTP). Caplacizumab treats the acute platelet–vWF interaction but does not address the underlying autoantibody against ADAMTS13 — recurrences are possible after drug discontinuation if ADAMTS13 has not recovered (noted in follow-up). The 30-day post-TPE treatment extension must be balanced against cumulative bleeding risk. Limited long-term safety data beyond the study drug treatment period. No OS benefit was formally powered — mortality events were few due to the rarity of the condition.

Clinical Context

Caplacizumab (Cablivi) received FDA approval in February 2019 for aTTP in adults (in combination with plasma exchange and immunosuppressive therapy). ISTH and ASH guidelines recommend caplacizumab for aTTP alongside plasma exchange and corticosteroids. Rituximab (to suppress ADAMTS13 autoantibodies) is used concurrently, particularly for refractory/relapsing disease. Caplacizumab does not replace TPE or rituximab but dramatically reduces the number of TPE sessions required and prevents early thromboembolic events during the window before ADAMTS13 recovery. It is now standard of care at TTP-experienced centers.

References

References: Scully M et al, NEJM 2019 (HERCULES primary)