Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other antithrombotic agents, ATC code: B01AX07.

Mechanism of action
Caplacizumab is a humanised bivalent Nanobody that consists of two identical humanised building blocks (PMP12A2hum1), genetically linked by a three-alanine linker, targeting the A1-domain of von Willebrand factor and inhibiting the interaction between von Willebrand factor and platelets. As such, caplacizumab prevents the ultra large von Willebrand factor-mediated platelet adhesion, which is characteristic of aTTP. It also affects the disposition of von Willebrand factor, leading to transient reductions of total von Willebrand factor antigen levels and to concomitant reduction of factor VIII:C levels during treatment.

Pharmacodynamic effects

Target inhibition
The pharmacologic effect of caplacizumab on target inhibition was assessed using two biomarkers for von Willebrand factor activity; ristocetin-induced platelet aggregation (RIPA) and ristocetin cofactor (RICO). Full inhibition of von Willebrand factor-mediated platelet aggregation by caplacizumab is indicated by RIPA and RICO levels dropping below 10% and 20%, respectively. All clinical studies with caplacizumab demonstrated rapid decreases in RIPA and/or RICO levels after the start of the treatment, with recovery to baseline levels within 7 days of discontinuation. The 10 mg subcutaneous dose in patients with aTTP elicited full inhibition of von Willebrand factor-mediated platelet aggregation, as evidenced by RICO levels of < 20% throughout the treatment period.

Target disposition
The pharmacologic effect of caplacizumab on target disposition was measured using von Willebrand factor antigen and factor VIII clotting activity (factor VIII:C) as biomarkers. Upon repeated administration of caplacizumab, a decrease of 30-50% in von Willebrand factor antigen levels was observed in clinical studies, reaching a maximum within 1-2 days of treatment. Because von Willebrand factor acts as a carrier for factor VIII, reduced von Willebrand factor antigen levels resulted in a similar reduction in factor VIII:C levels. The reduced von Willebrand factor antigen and FVIII:C levels were transient and returned to baseline upon cessation of treatment.

Clinical efficacy and safety

The efficacy and safety of caplacizumab in adults experiencing an episode of aTTP were established in 2 randomised, controlled studies: Phase III study ALX0681-C301 “HERCULES” and Phase II study ALX-0681-2.1/10 “TITAN”.

Efficacy

Study ALX0681-C301 (HERCULES)
In this double-blind, placebo-controlled study, patients with an episode of aTTP were randomised 1:1 to receive either caplacizumab or placebo in addition to daily plasma exchange and immunosuppression. Patients received a single intravenous bolus injection of 10 mg caplacizumab or placebo prior to the first plasma exchange on study. This was followed by daily subcutaneous injections of 10 mg caplacizumab or placebo after completion of each plasma exchange for the duration of the daily plasma exchange period and for 30 days thereafter. If at the end of this treatment period there was evidence of persistent underlying disease activity (indicative of an imminent risk for recurrence), treatment could be extended weekly for a maximum of 4 weeks, together with optimisation of immunosuppression. If a recurrence occurred while on study drug treatment, patients were switched to open-label caplacizumab. They were again treated for the duration of daily plasma exchange and for 30 days thereafter. If at the end of this treatment period there was evidence of ongoing underlying disease, open-label treatment with caplacizumab could be extended weekly for a maximum of 4 weeks, together with optimisation of immunosuppression. Patients were followed for 1 month after discontinuation of treatment. In case of recurrence during the follow up period (i.e. after all study drug treatment had been stopped), there was no re-initiation of study drug and the recurrence was to be treated according to the standard of care.

In this study, 145 patients experiencing an episode of aTTP were randomised (72 to caplacizumab and 73 to placebo). Patient age ranged from 18 to 79 years, with a mean of 46 years. Half of the patients were experiencing their first episode of aTTP. Baseline disease characteristics were typical of aTTP.

The median treatment duration with caplacizumab in the double blind period was 35 days.

Treatment with caplacizumab resulted in a statistically significant reduction in time to platelet count response (p<0.01). Patients treated with caplacizumab were 1.55 times more likely to achieve platelet count response at any given time point, compared to patients treated with placebo.

Treatment with caplacizumab resulted in a 74% reduction in the composite endpoint of the percentage of patients with aTTP-related death (0/72; placebo 3/73), exacerbation of aTTP (3/72; placebo 28/73), or at least one major thromboembolic event during study drug treatment (6/72; placebo 6/73) (p<0.0001). There were no deaths in the caplacizumab group and 3 deaths in the placebo group during the study drug treatment period.
The proportion of patients with a recurrence of aTTP (exacerbation or relapse) in the overall study period (including the 28 day follow-up after discontinuation of study drug treatment) was 67% lower in the caplacizumab group (9/72; relapse : 6/72) compared to the placebo group (28/73; relapse 0/73) (p<0.001).

No patients treated with caplacizumab (0/72) were refractory to treatment (defined as absence of platelet count doubling after 4 days of standard treatment and elevated LDH) compared to three patients treated with placebo (3/73).

Treatment with caplacizumab reduced the mean number of days of plasma exchange, the volume of plasma used, the mean length of Intensive Care Unit stay and the mean length of hospitalization during the study drug treatment period.

Table 2. Summary of number of days of plasma exchange (PE), total volume of PE used, number of days in hospital and ICU in the ITT population

Placebo      Caplacizumab
Number of days of Plasma Exchange (days)                  N              73             71 Mean (SE)      9.4 (0.81)     5.8 (0.51)
Total volume of plasma used (litre)                     N                73             71 Mean (SE)        35.93 (4.17)   21.33 (1.62)
Length of hospitalization (days)                        N                73             71 Mean (SE)        14.4 (1.22)    9.9 (0.70)
Number of days in ICU                                   N                27             28 Mean (SE)        9.7 (2.12)     3.4 (0.40)
N: number of patients evaluated; SE: Standard Error; ICU: Intensive Care Unit 
Immunogenicity
In clinical studies, up to 11% of patients developed treatment-emergent anti-drug antibodies (ADA).
No impact on clinical efficacy was observed and no serious adverse events were found to be associated with these ADA responses.

Paediatric population
See section 4.2 for information on paediatric use and section 5.2 for results of modelling and simulation studies for paediatric patients. There are no clinical data for paediatric patients.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
The pharmacokinetics of caplacizumab have been investigated in healthy subjects after single intravenous infusions and after single and repeated subcutaneous injections. Pharmacokinetics in patients with aTTP were investigated upon single intravenous and repeated subcutaneous injections.

Pharmacokinetics of caplacizumab appear as non-dose proportional, as characterized by target- mediated disposition. In healthy volunteers receiving 10 mg caplacizumab subcutaneously once daily, the maximum concentration was observed at 6-7 hours post-dose and steady-state was reached following the first administration, with minimal accumulation.

Absorption
After subcutaneous administration, caplacizumab is rapidly and almost completely absorbed (estimated F> 0.901) in the systemic circulation.

Distribution
After absorption, caplacizumab binds to the target and distributes to well perfused organs. In patients with aTTP the central volume of distribution was estimated at 6.33 L.
Biotransformation/Elimination
The pharmacokinetics of caplacizumab depend on the expression of the target von Willebrand factor.
Higher levels of von Willebrand factor antigen, such as in patients with aTTP, increase the fraction of drug-target complex retained in the circulation. The t1/2 of caplacizumab is, therefore, concentration- and target level-dependent. Target-bound caplacizumab is assumed to be catabolised within the liver, whereas unbound caplacizumab is assumed to be renally cleared.

Characteristics in specific groups
The pharmacokinetics of caplacizumab were determined using a population pharmacokinetic analysis on pooled pharmacokinetic data. Body weight was allometrically included in the model. Differences in the different subpopulations were investigated. In studied populations; gender, age, blood group and race did not affect the pharmacokinetics of caplacizumab.

Renal or hepatic impairment
No formal study of the effect of hepatic or renal impairment on the pharmacokinetics of caplacizumab has been conducted. In the population PK/PD model, renal function (CRCL) had a statistically significant effect resulting in limited increase in predicted exposure (AUCss) in severe renal impairment. In the clinical studies of patients with TTP, those with renal impairment did not show additional risk of adverse events.

Paediatric population
Based on data pooled from clinical studies in adults, a pharmacokinetic-pharmacodynamic (PK/PD) population model was developed, describing the interaction between caplacizumab and von Willebrand factor antigen (vWF:Ag), in different adult populations following intravenous and subcutaneous administration of caplacizumab at various dose levels. For children aged 2 to below 18 years of age, simulations were performed based on this PK/PD model predicting that exposure and suppression of vWF:Ag are expected to be similar to those in adults when 10 mg/day is used in children with a bodyweight of ≥40 kg, and when 5 mg/day is used in children with a bodyweight of <40 kg.