Mechanism Of Action
Caplacizumab-yhdp targets the A1-domain of vWF, and inhibits the interaction between vWF
and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption.
Ristocetin cofactor (RICO) activity was used to assess vWF activity. Subcutaneous doses of caplacizumab-yhdp at greater than or equal to the approved recommended dosage to healthy subjects and patients with aTTP decreased RICO activity levels to below 20% approximately 4 hours post-dose. RICO activity returned to baseline values within 7 days of drug discontinuation.
Caplacizumab-yhdp decreased vWF antigen and factor VIII:C levels. These reductions were transient and returned to baseline upon cessation of treatment.
Caplacizumab-yhdp pharmacokinetics depends on the expression of the target vWF and are not dose proportional. Higher levels of vWF antigen increase the fraction of drug-target complex retained in the circulation. Steady-state was reached following the first administration of CABLIVI in healthy subjects, with minimal accumulation. Following a single subcutaneous dose of 10 mg caplacizumab-yhdp to healthy subjects the mean (CV%) peak concentration (Cmax) was 528 (20%) ng/ml and AUC0-24 was 7951 (16%). Following subcutaneous dosing of 10 mg caplacizumab-yhdp daily for 14 days to healthy subjects, the mean (CV%) Cmax was 348 (30%) ng/ml and AUC0-τ was 6808 (26%) hr·ng/ml.
The bioavailability of subcutaneous caplacizumab-yhdp is approximately 90%.
The maximum concentration was observed 6 to 7 hours after subcutaneous dosing of 10 mg caplacizumab-yhdp once daily in healthy subjects.
Caplacizumab-yhdp central volume of distribution is 6.33 L in patients with aTTP.
The half-life of caplacizumab-yhdp is concentration and target-level dependent.
The available data suggest target-bound caplacizumab-yhdp is metabolized within the liver. Because caplacizumab-yhdp is a monoclonal antibody fragment, it is expected to be catabolized by various proteolytic enzymes.
The available nonclinical data suggest unbound caplacizumab-yhdp is cleared renally.
No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed in patients with pre-existing or treatment-emergent anti-drug antibodies.
No clinically significant differences in the pharmacokinetics of caplacizumab-yhdp were observed based on age (18 to 79 years), sex (66% females), race (White (83%) and Black
(17%)), blood group (O (41%) and other groups (59%)), or renal impairment (mild [CrCl: 60 to 90 mL/min], moderate [CrCl: 30 to 60 mL/min] or severe [CrCl: 15 to 30 mL/min]). The effect of hepatic impairment on the pharmacokinetics of caplacizumab-yhdp is unknown [see Use In Specific Populations].
Drug Interaction Studies
No dedicated drug-drug interaction studies with caplacizumab-yhdp have been conducted.
The efficacy of CABLIVI for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP) in combination with plasma exchange and immunosuppressive therapy was established in a pivotal multicenter, randomized, double-blind, placebo-controlled trial (HERCULES) (NCT02553317).
A total of 145 patients were enrolled in the HERCULES study; the median age was 45 (range: 18 to 79) years, 69% were female, 73% were White. Patients were randomized to either CABLIVI (n=72) or placebo (n=73). Patients in both groups received plasma exchange and immunosuppressive therapy. Patients were stratified according the severity of neurological involvement (Glasgow Coma Scale score ≤12 or 13 to 15). Patients with sepsis, infection with E. coli 0157, atypical hemolytic uremic syndrome, disseminated intravascular coagulation or congenital thrombotic thrombocytopenic purpura were not eligible for enrollment.
Patients received a single 11 mg CABLIVI bolus intravenous injection or placebo prior to the first plasma exchange on study, followed by a daily subcutaneous injection of 11 mg CABLIVI or placebo after completion of plasma exchange, for the duration of the daily plasma exchange period and for 30 days thereafter. If after the initial treatment course, sign(s) of persistent underlying disease such as suppressed ADAMTS13 activity levels remained present, treatment was extended for 7 day intervals for a maximum of 28 days.
The median treatment duration with CABLIVI was 35 days.
The clinical trial protocol specified the CABLIVI dose as 10 mg, to be delivered by withdrawing all of the reconstituted solution from the vial and administering the full amount. A dose recovery study showed that the mean dose that can be withdrawn from a vial is 11 mg. Therefore, based on the dose recovery study, the mean dose delivered in the trial was 11 mg.
The efficacy of CABLIVI in patients with aTTP was established based on time to platelet count response (platelet count ≥150,000/μL followed by cessation of daily plasma exchange within 5 days). Time to platelet count response was shorter among patients treated with CABLIVI, compared to placebo.
Figure 1: Platelet Response over Time
Treatment with CABLIVI resulted in a lower number of patients with TTP-related death, recurrence of TTP, or at least one treatment-emergent major thromboembolic event (a composite endpoint) during the treatment period (see Table 2).
Table 2: Patients in the HERCULES Study with aTTP-Related Death, a Recurrence of aTTP, or at Least One Treatment-Emergent Major Thromboembolic Event During Study Drug Treatment Period (ITT population)
|Number of patients with
| TTP-related death
| Recurrence of TTP (exacerbation)†
| At least one treatment-emergent major thromboembolic event
N = number of patients within the population of interest (by treatment group); n = number of patients with events; TTP = thrombotic thrombocytopenic purpura; ITT = intent to treat; * based on 71 patients who received at least one dose of study drug.
† Exacerbation defined as thrombocytopenia after initial recovery of platelet count (platelet count ≥150,000/μL with subsequent stop of daily plasma exchange within 5 days) that required reinitiation of daily plasma exchange during the 30-day post daily plasma exchange period.
‡ p <0.0001
The proportion of patients with a recurrence of TTP in the overall study period (the drug treatment period plus the 28-day follow-up period after discontinuation of drug treatment) was lower in the CABLIVI group (9/72 patients [13%]) compared to the placebo group (28/73 patients [38%] (p<0.001). In the 6 patients in the CABLIVI group who experienced a recurrence of TTP during the follow-up period (i.e., a relapse defined as recurrent thrombocytopenia after initial recovery of platelet count (platelet count ≥150,000/μL) that required reinitiation of daily plasma exchange, occurring after the 30-day post daily plasma exchange period), ADAMTS13 activity levels were <10% at the end of the study drug treatment, indicating that the underlying immunological disease was still active at the time CABLIVI was stopped.