Regulatory Decision Summary for Cablivi

Authorization was based on one Phase III pivotal randomized double-blind placebo-controlled study (HERCULES) and one Phase II randomized single-blind placebo-controlled study (TITAN) in patients with acute episode of aTTP and three Phase I studies in healthy volunteers (studies ALX-0081-01/06, ALX-0681-1.1/08, and ALX0681-C102).

In the HERCULES study, eligible patients were randomized to receive either 11 mg Cablivi (n = 72) or placebo (n = 73), in addition to daily plasma exchange (PE) and immunosuppression. Patients received a single intravenous bolus injection of Cablivi or placebo prior to the first PE on study. This was followed by daily subcutaneous injections of Cablivi or placebo after completion of each plasma exchange for the duration of the daily PE period and for 30 days thereafter. If at the end of this treatment period there was evidence of persistent underlying immunological disease activity such as suppressed ADAMTS13 activity levels, treatment could be extended weekly for a maximum of 4 weeks together with optimization of immunosuppression.

Patients who experienced a recurrence of aTTP while on study drug treatment were switched to open-label Cablivi. They were again treated for the duration of daily PE and for 30 days thereafter. If at the end of this treatment period there was evidence of ongoing underlying immunological disease, open-label treatment with Cablivi could be extended weekly for a maximum of 4 weeks together with optimization of immunosuppression.

TITAN had a similar study design, patient`s population and median duration of exposure as those of HERCULES with no treatment extension and no treatment switch to open-label Cablivi during the study drug treatment. Eligible patients were randomized to either the caplacizumab group (n = 36) or the placebo group (n = 39). The follow-up period was up to 12 month after the last dose of study drug.

The efficacy and safety of Cablivi in combination with plasma exchange and immunosuppressants was established in the HERCULES study and supported by the TITAN study.

Compared to placebo treatment, Cablivi significantly reduced the rate of exacerbation and delayed the occurrence of exacerbation during treatment period.

The Cablivi treatment was generally well tolerated in patients with aTTP in clinical studies. Bleeding-related adverse reactions were among the most reported adverse reactions. For clinically significant bleeding, it is recommended to interrupt the use of Cablivi and, if needed, administer vWF concentrate. Cases of relapse of aTTP shortly after discontinuation of Cablivi treatment were also noted, and therefore it is recommended to monitor patients after stopping or interrupting Cablivi treatment.

Overall, the results of the of the HERCULES study support a positive benefit risk profile for Cablivi when combined with plasma exchange and immunosuppression in the treatment of patients with aTTP.