What is Caplacizumab?

Caplacizumab: A Targeted Therapy for Acquired Thrombotic Thrombocytopenic Purpura

Caplacizumab (CABLIVI) is a von Willebrand factor (vWF)-directed antibody fragment that targets the A1-domain of vWF, inhibiting the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption in acquired thrombotic thrombocytopenic purpura (aTTP). 1

Mechanism of Action and Structure

• Caplacizumab-yhdp is a humanized antibody fragment consisting of two identical humanized building blocks linked by a three-alanine linker, with an approximate molecular weight of 28 kDa 1
• It specifically targets the A1-domain of von Willebrand factor, preventing its interaction with platelets, which is the final and obligatory pathway for platelet aggregation 1, 2
• By inhibiting this interaction, caplacizumab prevents microthrombosis formation in aTTP patients, offering a direct and rapid therapeutic intervention 2

Clinical Use and Indications

• Caplacizumab is indicated for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in adults, in conjunction with plasma exchange (PEX) and immunosuppressive therapy 1, 3
• It is particularly recommended for Grade 4 aTTP with life-threatening consequences (e.g., CNS hemorrhage, thrombosis, embolism, or renal failure) 4
• The drug should be administered in conjunction with hematology consultation and therapeutic plasma exchange according to existing guidelines 4

Dosing and Administration

• Initial dose: 10 mg intravenous loading bolus before plasma exchange 3
• Maintenance: 10 mg subcutaneous injection daily after each plasma exchange 3
• Treatment should continue daily for at least 30 days after completing plasma exchange 3
• Treatment may be discontinued if there is no exacerbation within 3-5 days after stopping PEX 4

Pharmacokinetics

• Bioavailability: Approximately 90% for subcutaneous administration 1
• Maximum concentration: Observed 6-7 hours after subcutaneous dosing 1
• Distribution: Central volume of distribution is 6.33 L in aTTP patients 1
• Metabolism: Target-bound caplacizumab is metabolized within the liver and catabolized by various proteolytic enzymes 1
• Elimination: Unbound caplacizumab is cleared renally; half-life is concentration and target-level dependent 1
• No dose adjustments are needed based on age, sex, race, blood group, or renal impairment 1

Clinical Efficacy

• In clinical trials, caplacizumab demonstrated faster normalization of platelet count compared to placebo (2.69 days vs. 2.88 days) 3
• Patients receiving caplacizumab had a 74% lower incidence of composite outcome events (death, recurrence of TTP, or thromboembolic events) compared to placebo 3
• The percentage of patients who experienced TTP recurrence at any time during trials was 67% lower with caplacizumab than with placebo (12% vs. 38%) 3
• No patients developed refractory disease in the caplacizumab group compared to three patients in the placebo group 3
• Patients treated with caplacizumab required less plasma exchange and had shorter hospitalization 3

Adverse Effects and Safety

• The most common adverse effect is mucocutaneous bleeding, reported in 65% of patients receiving caplacizumab compared to 48% in the placebo group 3
• Due to its mechanism of action, caplacizumab increases the risk of bleeding; close monitoring for bleeding is recommended 1
• In case of overdose, von Willebrand factor concentrate may be considered to correct hemostasis 1
• Caplacizumab should be used with caution in patients with severe hepatic impairment due to potential increased bleeding risk 1

Special Populations

• Pregnancy: No human data available; animal studies showed no adverse developmental outcomes 1
• Lactation: No information on presence in human milk; consider benefits of breastfeeding along with clinical need 1
• Pediatric use: Safety and effectiveness in pediatric patients have not been established 1
• Geriatric use: Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine differential response 1
• Hepatic impairment: Close monitoring for bleeding is recommended in patients with severe hepatic impairment 1

Clinical Context and Management Algorithm

For patients with suspected TTP:

1. Obtain immediate hematology consultation 4
2. Assess for evidence of RBC destruction (schistocytosis), thrombocytopenia, and clinical consequences 4
3. Test for ADAMTS13 activity and inhibitor titer 4, 5
4. For Grade 4 TTP (life-threatening consequences):
   • Initiate therapeutic plasma exchange according to existing guidelines 4
   • Administer methylprednisolone 1g IV daily for 3 days 4
   • Consider caplacizumab if ADAMTS13 activity level is normal, with an inhibitor or elevated anti-ADAMTS13 IgG 4
   • May offer rituximab as part of the treatment regimen 4, 5
5. Monitor platelet count response and continue treatment until ADAMTS13 recovery 5
6. If no exacerbation within 3-5 days after stopping PEX, taper steroids over 2-3 weeks, complete course of rituximab (if receiving), and discontinue caplacizumab 4

Caplacizumab represents a significant advance in the management of aTTP, reducing mortality and morbidity when used in conjunction with standard therapies of plasma exchange and immunosuppression 2, 5.