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The efficacy and safety of CABLIVI were established in a pivotal clinical study1-4

HERCULES Study Design

A pivotal, phase 3, double-blind, randomized controlled trial of 145 patients with aTTP. Patients were given PEX and immunosuppressive therapy in the form of corticosteroid treatment. Other immunosuppressive treatments such as rituximab were permitted but not required.* Patients were then randomized to receive CABLIVI (72) or placebo (73) for the duration of daily PEX and 30 days thereafter. Patients could receive extended treatment for up to 28 days if signs of underlying disease persisted, such as suppressed ADAMTS13 activity levels.1,2

A pivotal, phase 3, double-blind, randomized controlled trial of 145 patients with aTTP. Patients were randomized to receive CABLIVI (72) or placebo (73) fo the duration of daily PEX and 30 days thereafter
A pivotal, phase 3, double-blind, randomized controlled trial of 145 patients with aTTP. Patients were randomized to receive CABLIVI (72) or placebo (73) fo the duration of daily PEX and 30 days thereafter

Key efficacy endpoints1,2

Stopwatch

Primary endpoint

Time to platelet count normalization§

Life Line

Secondary endpoint

Composite of aTTP-related events during study-drug period, including:
aTTP-related death, recurrence, and ≥1 major TE event

Exclamation Point

Secondary endpoint

Recurrence during overall study period

Key characteristics2

Select Demographic and Baseline Characteristics in the Study Population
Characteristic CABLIVI
n (%)
Placebo
n (%)
Total
n (%)
Immunosuppressive Therapy—no. (%)
Glucocorticoids 69 (96) 71 (97) 140 (97)
Rituximab 28 (39) 35 (48) 63 (43)
Other 12 (16) 3 (3) 15 (10)
Presenting Episode of TTP—no. (%)
Initial 48 (67) 34 (47) 82 (57)
Recurrent 24 (33) 39 (53) 63 (43)
ADAMTS13 Activity—no. (%)#
<10% 58 (81) 65 (89) 123 (85)
≥10% 13 (18) 7 (10) 20 (14)

Key Inclusion Criteria: ≥18 years of age; clinical diagnosis of aTTP; required initiation of daily PEX and received PEX prior to randomization.2,4

Key Exclusion Criteria: Platelet count ≥100x109/L or >30x109/L if serum creatinine level >200 µmol/L; known other causes of thrombocytopenia; congenital TTP, pregnancy, or breastfeeding; clinically significant active bleeding or high risk of bleeding; known chronic treatment with anticoagulant treatment; malignant arterial hypertension; life expectancy <6 months.2,4

aTTP=acquired thrombotic thrombocytopenic purpura; PEX=plasma exchange; TE=thromboembolic; TTP=thrombotic thrombocytopenic purpura.

*2 patients in each group did not receive any immunosuppressive therapy.

Daily PEX was variable based on platelet count normalization at ≥150,000/µL and physician discretion.4

Thrombocytopenia after initial recovery of platelet count (platelet count ≥150,000/µL) that required reinitiation of daily PEX was considered a recurrence. Recurrences were termed exacerbations if they occurred within 30 days of the last PEX and relapses if they occurred more than 30 days after the last PEX.2

§Platelet count normalization was defined as platelet count ≥150,000/µL with discontinuation of daily PEX 5 days thereafter.2

Other immunosuppressive therapies include, for CABLIVI and placebo respectively: mycophenolate mofetil (6, 0), hydroxychloroquine (2, 1), bortezomib (2, 0), cyclophosphamide (1, 1), cyclosporin (1, 1).

The difference between the trial groups in the percentage of patients who presented with an initial episode as compared with a recurrent episode was significant (P<0.05).2

#The normal range of ADAMTS13 activity used in the trial was 50% to 130%. As a result of the requirement for previous plasma exchange, baseline ADAMTS13 activity was higher than that measured locally at the time of admission in some cases. When available, ADAMTS13 activity levels that were locally measured at the time of admission were obtained, and the lower value of the baseline and admission values is represented.2

IMPORTANT SAFETY INFORMATION AND INDICATIONS

CONTRAINDICATIONS:

CABLIVI is contraindicated in patients with a previous severe hypersensitivity reaction to caplacizumab-yhdp or to any of its excipients. Hypersensitivity reactions have included urticaria.

WARNINGS AND PRECAUTIONS:

Bleeding Risk:

  • CABLIVI increases the risk of bleeding. In clinical studies, severe bleeding adverse reactions of epistaxis, gingival bleeding, upper gastrointestinal hemorrhage, and metrorrhagia were each reported in 1% of subjects. Overall, bleeding events occurred in approximately 58% of patients on CABLIVI versus 43% of patients on placebo. The risk of bleeding is increased, in patients with underlying coagulopathies and concomitant use of CABLIVI with drugs affecting hemostasis.
  • If clinically significant bleeding occurs, interrupt use of CABLIVI. Von Willebrand factor concentrate may be administered to rapidly correct hemostasis. If CABLIVI is restarted, monitor closely for signs of bleeding.
  • Withhold CABLIVI for 7 days prior to elective surgery, dental procedures or other invasive interventions. If emergency surgery is needed, the use of von Willebrand factor concentrate may be considered to correct hemostasis. After the risk of surgical bleeding has resolved, and CABLIVI is resumed, monitor closely for signs of bleeding.

ADVERSE REACTIONS:

The most common adverse reactions (>15% of patients) were epistaxis (29%), headache (21%) and gingival bleeding (16%).

CONCOMITANT USE OF ANTICOAGULANTS:

Concomitant use of CABLIVI with any anticoagulant may increase the risk of bleeding. Assess and monitor closely for bleeding with concomitant use.

PREGNANCY:

There are no available data on CABLIVI use in pregnant women to inform a drug associated risk of major birth defects and miscarriage.

  • Fetal/neonatal adverse reactions: CABLIVI may increase the risk of bleeding in the fetus and neonate. Monitor neonates for bleeding.
  • Maternal adverse reactions: All patients receiving CABLIVI, including pregnant women, are at risk for bleeding. Pregnant women receiving CABLIVI should be carefully monitored for evidence of excessive bleeding.

INDICATIONS:

CABLIVI (caplacizumab-yhdp) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenic purpura (aTTP), in combination with plasma exchange and immunosuppressive therapy.