Cablivi is indicated for the treatment of adults and adolescents of 12 years of age and older weighing at least 40 kg experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP), in conjunction with plasma exchange and immunosuppression.

Treatment with Cablivi should be initiated and supervised by physicians experienced in the management of patients with thrombotic microangiopathies.

Posology

First dose

Intravenous injection of 10 mg of caplacizumab prior to plasma exchange.

Subsequent doses

Daily subcutaneous administration of 10 mg of caplacizumab after completion of each plasma exchange for the duration of daily plasma exchange treatment, followed by daily subcutaneous injection of 10 mg of caplacizumab for 30 days after stopping daily plasma exchange treatment.

If at the end of this period there is evidence of unresolved immunological disease, it is recommended to optimise the immunosupression regimen and continue daily subcutaneous administration of 10 mg of caplacizumab until the signs of underlying immunological disease are resolved (e.g. sustained normalisation of ADAMTS13 activity level).

In the clinical development program, caplacizumab has been administered daily for up to 71 days consecutively. Data on re-treatment with caplacizumab are available (see section 5.1).

Missed dose

If a dose of Cablivi is missed, it can be administered within 12 hours. If more than 12 hours have passed since the dose was to have been given, the missed dose should NOT be administered and the next dose should be administered per the usual dosing schedule.

Special populations

Renal impairment

No dose adjustment is necessary for patients with renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with hepatic impairment (see section 5.2). See section 4.4 for special considerations in patients with severe hepatic impairment.

Elderly

While experience with the use of caplacizumab in the elderly is limited, there is no evidence to suggest that dose adjustment or special precautions are needed for elderly patients (see section 5.2).

Paediatric population

The safety and efficacy of caplacizumab in the paediatric population have not been established in clinical trials. The posology of Cablivi in adolescents of 12 years of age and older weighing at least 40 kg is the same as in adults (see section 5.2). No recommendations can be made on the posology of Cablivi for paediatric patients below 40 kg of body weight.

Method of administration

The first dose of Cablivi is to be administered as an intravenous injection. Subsequent doses are to be administered via subcutaneous injection in the abdomen.

Injections into the area around the navel should be avoided and consecutive injections should not be administered in the same abdominal quadrant.

Patients or caregivers may inject the medicinal product after proper training in the subcutaneous injection technique.

For instructions on reconstitution of Cablivi before administration, see section 6.6.

Bleeding

Cablivi increases the risk of bleeding. Cases of major bleeding, including life-threatening and fatal bleeding have been reported in patients receiving caplacizumab, mainly in those using concomitant anti-platelet agents or anticoagulants. Caplacizumab should be used with caution in patients with underlying conditions that may predispose them to a higher risk of bleeding

In case of clinically significant bleeding, treatment with Cablivi should be interrupted. If needed, the use of von Willebrand Factor concentrate could be considered to correct hemostasis. Cablivi should only be restarted upon the advice of a physician experienced in the management of thrombotic microangiopathies. If Cablivi is restarted, monitor closely for signs of bleeding.

In the setting of concomitant use of oral anticoagulants, anti-platelet agents, thrombolytic drugs or heparin

The risk of bleeding is increased with concomitant use of Cablivi with drugs affecting hemostasis and coagulation. Initiation or continuation of treatment with oral anticoagulants (e.g., vitamin K antagonists or direct oral anticoagulants [DOAC] such as thrombin inhibitors or factor Xa inhibitors), anti-platelet agents, thrombolytic drugs such as urokinase, tissue plasminogen activator (t-PA) (e.g. alteplase) or heparin requires careful consideration and close clinical monitoring.

In patients with coagulopathies

Due to a potential increased risk of bleeding, use of Cablivi in patients with underlying coagulopathies (e.g. hemophilia, other coagulation factor deficiencies) must be accompanied by close clinical monitoring.

In patients undergoing surgery

If a patient is to undergo elective surgery, an invasive dental procedure or other invasive interventions, the patient must be advised to inform the physician or dentist that they are using caplacizumab and it is recommended to withhold treatment for at least 7 days before the planned intervention. The patient must also notify the physician who supervises the treatment with caplacizumab about the planned procedure. After the risk of surgical bleeding has resolved, and caplacizumab is resumed, the patient should be monitored closely for signs of bleeding.

If emergency surgery is needed, the use of von Willebrand Factor concentrate is recommended to correct hemostasis.

Severe hepatic impairment

No formal study with caplacizumab has been conducted in patients with severe acute or chronic hepatic impairment and no data regarding the use of caplacizumab in these populations are available. Use of Cablivi in this population requires a benefit/risk assessment and close clinical monitoring.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

No interaction studies evaluating use of caplacizumab with oral anticoagulants (e.g. vitamin K antagonists, direct oral anticoagulants [DOAC] such as thrombin inhibitors or factor Xa inhibitors), antiplatelet agents, thrombolytic drugs such as urokinase, tPA (e.g. alteplase) or heparin have been performed (See section 4.4 In the setting of concomitant use of oral anticoagulants, anti-platelet agents, thrombolytic drugs or heparin).

Pregnancy

There are no data on the use of caplacizumab in pregnant women. Studies in guinea pigs showed no effect of caplacizumab on the dams or foetuses (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Cablivi during pregnancy.

Breastfeeding

There are no data on the use of caplacizumab in breastfeeding women. It is unknown whether caplacizumab is excreted in human milk. A risk to the child cannot be excluded.

A decision must be made whether to discontinue breastfeeding or to abstain/discontinue from therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

The effects of caplacizumab on fertility in humans are unknown. In animal toxicology studies, no impact of caplacizumab on male and female fertility parameters was observed (see section 5.3).

Cablivi has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequent adverse reactions in the TITAN and HERCULES clinical trials were epistaxis, headache and gingival bleeding. The most common serious adverse reaction was epistaxis.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA system organ class and by frequency. Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to

< 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

*Bleeding events: see below

Description of selected adverse reactions

Bleeding

In clinical studies, bleeding events occurred in different body systems, independent of treatment duration. In the postmarketing setting, cases of major bleeding, including life-threatening and fatal bleeding have been reported in patients receiving caplacizumab, mainly in those using concomitant

anti-platelet agents or anticoagulants. In case of clinically significant bleeding, consider actions outlined in sections 4.4 and 4.9.

Reporting of suspected adverse reactions

To report any side effect(s):

In case of overdose, based on the pharmacological action of caplacizumab, there is the potential for an increased risk of bleeding. Close monitoring for signs and symptoms of bleeding is recommended. (see section 4.4).

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 ultralarge 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 3 randomised, controlled studies: Phase III study ALX0681-C301 “HERCULES”, Phase III study ALX0681-C302 “Post-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.

N: number of patients evaluated; SE: Standard Error; ICU: Intensive Care Unit

Study ALX0681-C302 (Post-HERCULES)

The Post-HERCULES study was a Phase III, 36-month follow-up study from HERCULES (parent study) to evaluate the long-term outcomes as well as the safety and efficacy of repeat use of caplacizumab in patients who experienced a recurrence of aTTP. Overall, 104 out of 108 patients who completed the parent study (75 who received caplacizumab in HERCULES, of whom 49 did not have aTTP recurrences prior to the enrollment in Post-HERCULES, and 29 who had received only standard of care (SoC) in HERCULES) entered the Post-HERCULES study in which patients attended twice yearly visits. Patients could receive open-label (OL) caplacizumab for the treatment of an aTTP recurrence along with SoC.

Overall, 19 patients had at least 1 recurrence of aTTP and six patients had a 2^nd recurrence. For patients treated with caplacizumab for a recurrence, all events of aTTP from the first recurrence episode were resolved or were resolving at the end of the study.

The overall safety profile of caplacizumab re-treatment was consistent with that observed in other clinical studies of aTTP.

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 modeling and simulation studies for paediatric patients. There are no clinical data for paediatric patients.

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 subcutaneoulsy 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.

Consistent with its mode of action, toxicology studies of caplacizumab have shown an increased bleeding tendency in guinea pigs (haemorrhagic subcutaneous tissue at the injection sites) and cynomolgus monkeys (haemorrhagic subcutaneous tissue at the injection sites, nose bleed, exaggerated menstrual bleeding, haematoma at sites of animal handling or experimental procedures, prolonged bleeding at injection sites). Furthermore, pharmacology-related decreases of von Willebrand factor antigen, and consequently factor VIII:C, were noted in cynomolgus monkeys and, to a lesser extent for factor VIII:C, in guinea pigs.

An embryo-foetal development study was conducted in guinea pigs, with no reported signs of toxicity. A follow-up toxicokinetic study in pregnant guinea pigs assessed exposure of caplacizumab in the dams and foetuses. The results indicated exposure to caplacizumab in dams and, to a much lesser extent, foetuses, with no reported effects on foetal development. Foetal exposure to caplacizumab in primates and humans remains uncertain, as proteins lacking an Fc portion are not thought to freely pass the placental barrier.

No studies have been performed to evaluate the mutagenic potential of caplacizumab, as such tests are not relevant for biologicals. Based on a carcinogenicity risk assessment, dedicated studies were not deemed necessary.

Dedicated animal studies assessing the effects of caplacizumab on male and female fertility have not been performed. In repeat-dose toxicity tests in cynomolgus monkeys, no impact of caplacizumab on fertility parameters in male (testicular size, sperm function, histopathological analysis of testis and epididymis) and female (histopathological analysis of reproductive organs, periodic vaginal cytology) animals was observed.

Powder
Sucrose
Citric acid anhydrous
Trisodium citrate dihydrate
Polysorbate 80

Solvent
Water for injections

In the absence of compatibility studies, Cablivi must not be mixed with other medicinal products.

Store in a refrigerator (2 °C - 8 °C).
Do not freeze.
Store in the original package in order to protect from light.
Cablivi may be stored at a temperature not above 25 °C for a single period of up to 2 months, but not beyond the expiry date. Do not return Cablivi to refrigerated storage after storage at room temperature.
For storage conditions of the reconstituted medicinal product, see section 6.3.

Powder
Vial (type I glass) with a stopper (butyl rubber), a seal (aluminium) and a cap (polypropylene), containing 10 mg of caplacizumab.

Solvent
Pre-filled syringe (type I glass cartridge closed with a bromobutyl rubber stopper) with 1 mL of water for injections.

Pack size

• Single pack containing 1 vial with powder, 1 pre-filled syringe with solvent, 1 vial adapter, 1 hypodermic needle (30 gauge) and 2 alcohol swabs.
• Multipack containing 7 single packs.
• Multidose pack containing 7 vials with powder, 7 pre-filled syringes with solvent, 7 vial adapters, 7 hypodermic needles (30 gauge) and 14 alcohol swabs.

Not all pack sizes may be marketed.

For both intravenous and subcutaneuous administration, reconstitute the powder contained in the vial using the vial adapter and all solvent in the pre-filled syringe. The solvent should be added slowly and mixed gently to avoid foaming of the solution. Allow the vial with connected syringe to stand on a surface for 5 minutes at room temperature.

The reconstituted solution is clear, colourless, or slightly yellowish. It must be visually inspected for particulate matter. Do not use solution exhibiting particulates.

Transfer the entire volume of the reconstituted solution back to the glass syringe and immediately administer the entire volume of the syringe (see section 6.3).

Cablivi is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.