Sanofi

The single-domain antibody (sdAb) drug Cablivi (caplacizumab) combined with plasma exchange and immunosuppressive therapy, for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) adult patients with acquired thrombotic thrombocytopenic purpura. The approval makes Cablivi the first drug in the United States to specialize in the treatment of aTTP.

Cablivi was acquired after Sanofi spent $4.8 billion on Belgian biotechnology Ablynx, which was approved by the European Union at the end of August 2018 for adult patients who have experienced an aTTP attack. The approval makes Cablivi the world's first approved sdAb drug and the first drug specifically designed to treat aTTP. Cablivi has been granted orphan drug qualifications for the treatment of aTTP in the United States and the European Union, as well as fast-track qualifications and priority review qualifications in the United States.

The active drug component of Cablivi is caplacizumab, which is a potent and selective bivalent anti-von Willebrand factor (vWF) sdAb, which can block the interaction between very large vWF polymer (ULvWF) and platelets. It has an immediate effect on platelet aggregation and the subsequent formation and accumulation of small blood clots (microclot). In patients with aTTP, this tiny blood clot can lead to severe thrombocytopenia, tissue ischemia, and organ dysfunction. This transient effect of Cablivi (immediate effect,) can not only dismantle the potential disease process, but also protect the clinical manifestations of aTTP patients.

The approval of Cablivi was based on data from the Phase III Clinical study HERCULES (NCT02553317). The study was a randomized, double-blind, placebo-controlled study of 145 adult patients with aTTP. In the study, patients were randomly assigned to Cablivi or placebo and received standard care regimens (plasma exchange and immunosuppressive therapy).

The results showed that: (1) in terms of the main endpoints, compared with placebo + standard nursing regimen, Cablivi combined with a standard nursing regimen significantly shortened the time to normalize platelet count (p ≤ 0.01); (2) compared with placebo + standard nursing regimen, Cablivi + standard nursing regimen significantly reduced aTTP-related deaths, aTTP recurrence, or at least one major thromboembolism event by 74 percent during the study period (p < 0.001); (3) Cablivi + a standard nursing regimen significantly reduced the recurrence of aTTP by 67% (p < 0.001); (4) during the study, there were 0 refractory diseases in the Cablivi group and 3 refractory diseases in the placebo group, although there was no significant difference (p ≤ 0.06); (5) compared with the placebo group, the normalization of three organ injury markers (lactate dehydrogenase, cardiac troponin I, serum creatinine) occurred earlier in Cablivi group (p did not detect significant due to stratified statistical test); (6) the use of plasma exchange in Cablivi group was significantly lower than that in the placebo group (mean 5.8 days vs 9.4 days, a decrease of 38%), and the stay in intensive care units (a decrease of 65 percent) and hospitals (a decrease of 31 percent) was shorter; (7) the safety of Cablivi was consistent with previous reports and accords with its mechanism of action, including the increased risk of bleeding, most commonly epistaxis and gingival bleeding.