CABLIVI is the first and only therapy targeted to prevent microthrombi in adults with aTTP/iTTP^1,2*

The pathophysiology of aTTP/iTTP poses a triple threat.^2,5,8,12-15 These are summarized as below:

1)	Autoantibody formation
2)	Autoantibody formation leading to ADAMTS13 inhibition resulting in uncleaved vWF (ULvWF)
3)	Microthrombi-driven risks caused by ULvWF binding to platelets to form ULvWF-platelets aggregates

PEX and immunosuppressive therapy directly address only 2 of the 3 aspects of the disease.^2,5,8,12-15

*aTTP is also known as iTTP. The terms can be used interchangeably.

The triple threat of aTTP/iTTP deserves a triple therapy regimen with CABLIVI, PEX, and immunosuppressive therapy^{1,2,5,8,12-15}

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CABLIVI MOA: The first of its kind

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Acquired thrombotic thrombocytopenic purpura, or aTTP, is a rare, rapidly progressing, life-threatening autoimmune disease. Left untreated, up to 90% of aTTP patients die.

Historical treatment includes plasma exchange and immunosuppressive therapy, which has improved prognosis. However, despite these treatments, the mortality rate remains high at 8 to 20%. In a large retrospective study, the median time from diagnosis to death was 9 days despite treatment with plasma exchange.

Symptoms of aTTP can be complex and variable. Most common signs include thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia, resulting from microvascular occlusion. Clinical manifestations of organ ischemia can include strokes, transient ischemic attacks, myocardial infarction, and renal and mesenteric ischemia.

aTTP is caused by the severe deficiency of a von Willebrand factor-cleaving protease, ADAMTS13. This deficiency is due to formation of autoantibodies directed against ADAMTS13. Normally, ADAMTS13 breaks apart ultra large strings of von Willebrand factor, known as vWF, into smaller pieces. In aTTP patients, however, ADAMTS13 is blocked by autoantibodies, thereby greatly increasing the amount of ultra large vWF in circulation. Thousands of circulating platelets bind to these ultra large vWF strings, forming platelet-rich blood clots within small blood vessels throughout the body. These small clots are known as microthrombi.

As of February 2019, CABLIVI became the newest treatment approved by the FDA for aTTP in combination with plasma exchange and immunosuppressive therapy. Plasma exchange removes vWF and autoantibodies and replenishes ADAMTS13. Immunosuppressive therapies are intended to inhibit anti-ADAMTS13 autoantibody production. Neither directly affects the binding of platelets to vWF.

CABLIVI is a monoclonal antibody fragment that was developed to inhibit microthrombi formation in aTTP by binding specifically to the A1 domain of vWF. CABLIVI blocks the interaction between vWF and platelets, thereby reducing both vWF-mediated platelet adhesion and platelet consumption. This inhibits the formation of microthrombi while the underlying autoimmune disease is treated with immunosuppressive therapy.

IMPORTANT SAFETY INFORMATION AND INDICATIONS

IMPORTANT SAFETY INFORMATION

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:

Hemorrhage:

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.
In the postmarketing setting cases of life-threatening and fatal bleeding were reported in patients receiving CABLIVI.
The risk of bleeding is increased in patients with underlying coagulopathies (e.g. hemophilia, other coagulation factor deficiencies). It is also increased with concomitant use of CABLIVI with drugs affecting hemostasis and coagulation.
Avoid concomitant use of CABLIVI with antiplatelet agents or anticoagulants. 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 OR ANTIPLATELET AGENTS:

Concomitant use of CABLIVI with any anticoagulant or antiplatelet agent may increase the risk of bleeding. Avoid concomitant use when possible. 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.

Please see accompanying full Prescribing Information.

CHOOSE CABLIVI ON DAY 1 IN COMBINATION WITH PEX AND IMMUNOSUPPRESSIVE THERAPY

CABLIVI can help make a difference

Discover results of added strength

Safety demonstrated in one
of the
largest aTTP/iTTP trials²⁶

Review CABLIVI safety

Who should not start CABLIVI?

CABLIVI is contraindicated in patients with a previous severe hypersensitivity to caplacizumab-yhdp or to any of its excipients
Withhold CABLIVI treatment 7 days prior to elective surgery, dental procedures, or other invasive interventions

ADAMTS13=a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; aTTP=acquired thrombotic thrombocytopenic purpura; ISTH=International Society on Thrombosis and Haemostasis; iTTP=immune-mediated thrombotic thrombocytopenic purpura; MOA=mechanism of action; PEX=plasma exchange; ULvWF=ultra-large von Willebrand factor; vWF=von Willebrand factor.

IMPORTANT SAFETY
INFORMATION AND INDICATIONS

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS:

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

IMPORTANT SAFETY
INFORMATION AND INDICATIONS

IMPORTANT SAFETY INFORMATION

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:

Hemorrhage:

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.
In the postmarketing setting cases of life-threatening and fatal bleeding were reported in patients receiving CABLIVI.
The risk of bleeding is increased in patients with underlying coagulopathies (e.g. hemophilia, other coagulation factor deficiencies). It is also increased with concomitant use of CABLIVI with drugs affecting hemostasis and coagulation.
Avoid concomitant use of CABLIVI with antiplatelet agents or anticoagulants. 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 OR ANTIPLATELET AGENTS:

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:

Please see Full Prescribing Information

Instructions for Use

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References: 1. CABLIVI Prescribing Information: Genzyme Corporation. 2. Scully M, Cataland SR, Peyvandi F, et al; for the HERCULES Investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346. 3. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2486-2495. doi:10.1111/jth.15006. 4. Grall M, Azoulay E, Galicier L, et al. Thrombotic thrombocytopenic purpura misdiagnosed as autoimmune cytopenia: causes of diagnostic errors and consequence on outcome. Experience of the French thrombotic microangiopathies reference centre. Am J Hematol. 2017;92(4):381-387. 5. Scully M, Hunt BJ, Benjamin S, et al. On behalf of British Committee for Standards in Haematology. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323-335. 6. Goel R, King KE, Takemoto CM, Ness PM, Tobian AAR. Prognostic risk-stratified score for predicting mortality in hospitalized patients with thrombotic thrombocytopenic purpura: national representative data from 2007 to 2012. Transfusion. 2016;56(6):1451-1458. 7. Peyvandi F, Scully M, Kremer Hovinga JA, et al. Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2017;15(7):1448-1452. 8. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846. 9. Masias C, Wu H, McGookey M, Jay L, Cataland S, Yang S. No major differences in outcomes between the initial and relapse episodes in patients with thrombotic thrombocytopenic purpura: the experience from the Ohio State University Registry. Am J Hematol. 2018;93(3):E73-E75. doi:10.1002/ajh.25002. 10. Schieppati F, Russo L, Marchetti M, et al. Low levels of ADAMTS-13 with high anti-ADAMTS-13 antibodies during remission of immune-mediated thrombotic thrombocytopenic purpura highly predict for disease relapse: a multi-institutional study. Am J Hematol. 2020;95(8):953-959. doi:10.1002/ajh.25845. 11. Knoebl P, Cataland S, Peyvandi F, et al. Efficacy and safety of open-label caplacizumab in patients with exacerbations of acquired thrombotic thrombocytopenic purpura in the HERCULES study. J Thromb Haemost. 2020;18(2):479-484. doi:10.1111/jth.14679. 12. Sayani FA, Abrams CS. How I treat refractory thrombotic thrombocytopenic purpura. Blood. 2017;130(14):1684. doi:10.1182/blood-2017-08-803171. 13. Kremer Hovinga JA, Coppo P, Lämmle B, Moake JL, Miyata T, Vanhoorelbeke K. Thrombotic thrombocytopenic purpura. Nat Rev Dis Primers. 2017;3:17020. doi:10.1038/nrdp.2017.20. 14. Holz J-B. The TITAN trial—assessing the efficacy and safety of an anti-von Willebrand factor Nanobody in patients with acquired thrombotic thrombocytopenic purpura. Transfus Apher Sci. 2012;46(3):343-346. 15. Azoulay E, Bauer PR, Mariotte E, et al; Nine-i Investigators. Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura. Intensive Care Med. 2019;45(11):1518-1539. doi:10.1007/s00134-019-05736-5. 16. Kremer Hovinga JA, Vesely SK, Terrell DR, Lämmle B, George JN. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood. 2010;115(8):1500-1511. doi:10.1182/blood-2009-09-243790. 17. Upreti H, Kasmani J, Dane K, et al. Reduced ADAMTS13 activity during TTP remission is associated with stroke in TTP survivors. Blood. 2019;134(13):1037-1045. doi:10.1182/blood.2019001056. 18. Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: an international working group consensus report. Blood. 2021;137(14):1855-1861. doi:10.1182/blood.2020009150. 19. Vincent J-L, Castro P, Hunt BJ, et al. Thrombocytopenia in the ICU: disseminated intravascular coagulation and thrombotic microangiopathies—what intensivists need to know. Crit Care. 2018;22(1):158. 20. Chiasakul T, Cuker A. Clinical and laboratory diagnosis of TTP: an integrated approach. Hematology Am Soc Hematol Educ Program. 2018;2018(1):530-538. 21. Canpolat N. Hemolytic uremic syndrome. Turk Pediatri Ars. 2015;50(2):73-82. 22. Venugopal A. Disseminated intravascular coagulation. Indian J Anaesth. 2014;58(5):603-608. 23. Wada H, Matsumoto T, Suzuki K, et al. Differences and similarities between disseminated intravascular coagulation and thrombotic microangiopathy. Thromb J. 2018;16:14. 24. Cataland SR, Wu HM. How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood. 2014;123(16):2478-2484. 25. Laurence J, Haller H, Mannucci PM, Nangaku M, Praga M, de Cordoba SR. Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol. 2016;14 Suppl 11(11):2-15. 26. Supplement to: Scully M, Cataland SR, Peyvandi F, et al; for the HERCULES Investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346. doi:10.1056/NEJMoa1806311. 27. Protocol for: Scully M, Cataland SR, Peyvandi F, et al; for the HERCULES Investigators. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-346. doi:10.1056/NEJMoa1806311. 28. CABLIVI [instructions for use]. Cambridge, MA: Genzyme Corporation. 29. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of thrombotic thrombocytopenic purpura. J Thromb Haemost. 2020;18(10):2496-2502. doi:10.1111/jth.15010 30. Centers for Medicare & Medicaid Services. ICD-10-CM/PCS MS-DRGv37 Definitions Manual: MDC 8 Diseases & Disorders of the Musculoskeletal System & Connective Tissue Disorders. https://www.cms.gov/icd10m/version37-fullcode-cms/fullcode_cms/P0213.html. Updated September 12, 2019. Accessed January 9, 2023. 31. Centers for Medicare & Medicaid Services. 2023 ICD-10-CM. https://www.cms.gov/files/zip/2023-code-tables-tabular-and-index.zip. Updated July 27, 2022. Accessed January 9, 2023. 32. Centers for Medicare & Medicaid Services. 2023 ICD-10-PCS. https://www.cms.gov/files/zip/2023-icd-10-pcs-code-tables-and-index.zip. Accessed January 9, 2023.

CABLIVI is the first and only therapy targeted to prevent microthrombi in adults with aTTP/iTTP1,2*

The triple threat of aTTP/iTTP deserves a triple therapy regimen with CABLIVI, PEX, and immunosuppressive therapy1,2,5,8,12-15

CABLIVI MOA: The first of its kind

Hemorrhage:

Hemorrhage:

CABLIVI is the first and only therapy targeted to prevent microthrombi in adults with aTTP/iTTP^1,2*

The triple threat of aTTP/iTTP deserves a triple therapy regimen with CABLIVI, PEX, and immunosuppressive therapy^{1,2,5,8,12-15}