Brand Name


Pharmacological Class

von Willebrand factor (vWF)–directed single-domain antibody fragment (Nanobody® technology)


Acquired thrombotic thrombocytopenic purpura


Caplacizumab was granted orphan drug status for aTTP in 2009.22 It represents the first-in-class Nanobody® and the first vWF blocker to win FDA approval.93 aTTP is a rare and potentially fatal autoimmune blood clotting disorder caused by the development of antibodies against ADAMTS13, a vWF-cleaving proteinase.94,95 Lowered ADAMTS13 activity leads to the build-up of ultralarge vWF multimers and the formation of life-threatening thrombotic microangiopathies.9496 Nanobodies® are a proprietary class of small, sdAb fragments that were first engineered from the variable region of camelid heavy-chain-only antibodies.97,98 While retaining antigen-binding properties, Nanobodies® lack the heavy chain structure of their precursors, which gives them a potential size advantage to reach therapeutic targets in tight spaces.99101

Caplacizumab is a humanized bivalent sd antibody produced in Escherichia coli by recombinant DNA technology. It consists of two identical globular components (PMP12A2hum1)102 connected by a tri-alanine linker (see reference 98 for a schematic drawing). Caplacizumab targets the A-1 domain of vWF to block the interaction of vWF with platelet glycoprotein Ib-IX-V receptors and thereby reduces vWF-mediated platelet adhesion.32,94,97,102105 Its small molecular size (28 kDa) is thought to enhance delivery to vWF expressed on microvascular endothelial cells under high shear stress conditions.95

Caplacizumab is intended for use in conjunction with immunosuppression plus daily plasma exchanges until platelet counts recover. It is given urgently by intravenous push administration prior to the first plasma exchange, continued by subcutaneous injection after the first and every other exchange, and then extended by an additional 30–58 days to support the recovery of ADAMTS13 proteinase activity.32 In plasma, caplacizumab is thought to bind and neutralize vWF within approximately 5 minutes. It is expected to be rapidly catabolized by proteolytic enzymes with negligible excretion of unchanged drug via the urine.32,95,103 The mean terminal half-life is 19.2 ± 7.5 h.95 Bleeding is the most serious potential unwanted effect and may require rescue therapy with vWF concentrates.32,96

FDA approval of caplacizumab was grated on the basis of a multicenter, randomized, double-blind, placebo-controlled trial (HERCULES;96 NCT02553317)106 that randomized 145 patients (72 to caplacizumab; 73 to placebo).32 Treatment with caplacizumab resulted in a statistically significant reduction in time-to-platelet count response (p<0.01); a 74% reduction in a composite endpoint (composed of the percentage of patients with aTTP-related death, exacerbation, or at least one major thromboembolic event [p<0.0001]); and a 67% lower recurrence rate (p<0.001).96,102 The drug cost for treating a typical aTTP episode with caplacizumab is expected to be ∼$270,000.107

Further Reading in Goodman & Gilman