Sickle Cell Disease (SCD)

Adakveo® (crizanlizumab-tmca) is a prescription medicine indicated for preventing vaso-occlusive crises (VOCs) in patients aged 16 years and older with sickle cell disease.^1,2 Adakveo was developed by Novartis Pharmaceuticals and was approved by the US Food and Drug Administration (FDA) in November 2019.³

Sickle cell disease, which is inherited in autosomal-recessive fashion, is caused by mutations in the gene that encodes the β-globin subunit of hemoglobin.³  The red blood cells (RBCs) of affected individuals carry an abnormal form of hemoglobin, hemoglobin S (HbS), rather than the normal form, hemoglobin A. HbS polymerization affects RBC membrane structure and function, resulting in deformed RBCs with increased viscosity.⁴ When the abnormal RBCs adhere to the vascular endothelium, the vessels become obstructed.^3,4 Patients with sickle cell disease experience recurrent episodes of pain during VOCs, which cause significant morbidity and mortality.³

Get full prescribing information for Adakveo on MPR’s monograph page.

Mechanism of Action and Use of Crizanlizumab-tmca

Crizanlizumab-tmca is a humanized immunoglobulin G2 kappa monoclonal antibody that binds to P-selectin, inhibiting the interaction of P-selectin with its ligands, such as P-selectin glycoprotein ligand-1 (PSGL-1) .^1-3 P-selectin, a cell adhesion molecule, is involved in the adhesion of sickle RBCs, as well as platelets and leukocytes, to the endothelium. Even though the mechanisms leading to VOC are not fully described, it has been shown that P-selectin is expressed at higher levels in patients with sickle cell disease.³ By binding P-selectin on the surface of activated endothelium and platelets, crizanlizumab-tmca disrupts the interactions between endothelial cells, RBCs, platelets, and leukocytes, thereby preventing VOCs.¹

Adakveo is supplied as a sterile solution for dilution and also in 10-mL vials that contain 100 mg of drug. The recommended dose is 5 mg/kg, which should be administered as an intravenous infusion for 30 minutes at week 0 and week 2. It should subsequently be administered every 4 weeks.²

Crizanlizumab-tmca in Clinical Trials

The safety and efficacy of crizanlizumab-tmca, with or without hydroxyurea therapy, were studied in a 52-week, multicenter, randomized, placebo-controlled, double-blind phase II trial, SUSTAIN (NCT01895361).⁵ The study enrolled 198 patients aged 16 to 65 years with all genotypes of sickle cell disease. The patients had experienced 2 to 10 pain crises in the past 12 months. They were randomized in a 1:1:1 ratio to Adakveo at 5 mg/kg, Adakveo at 2.5 mg/kg, or placebo, administered as recommended.⁵ Results of the trial showed that the median annual rate of VOCs (the primary endpoint) was lower in the patients who received Adakveo at 5 mg/kg than in the patients who received placebo (1.63% vs 2.98%). The median time to first VOC was longer in the patients treated with Adakveo at 5 mg/kg than in those who received placebo (4.1 vs 1.4 months).The median annual number of days hospitalized was lower in the patients who were receiving Adakveo at 5 mg/kg (4.00 vs 6.87 days).⁵ Treatment with Adakveo was also associated with a lower annual number of VOCs requiring care in a medical facility (2.3 vs 2.7 events per person). In a follow-up study, the time to first VOC in the patients who received Adakveo at 5 mg/kg was similar to that in the SUSTAIN trial.³ 

Two multicenter and open-label phase II clinical trials are currently ongoing. The first is evaluating the pharmacokinetics and pharmacodynamics of crizanlizumab-tmca in patients with sickle cell disease causing VOCs (NCT03264989). The second is assessing the appropriate dose, with or without hydroxyurea, in sequential and descending age groups of pediatric patients with VOCs (NCT03474965). A phase III clinical trial assessing the efficacy and safety of 2 doses of crizanlizumab-tmca, with and without hydroxyurea (STAND trial, NCT03814746), was started in 2019.³

The administration of crizanlizumab-tmca can cause severe adverse reactions, including infusion-related reactions. Crizanlizumab may also be immunogenic.² The drug was well tolerated by patients participating in the SUSTAIN trial. Reactions associated with infusion occurred in 3% of the patients treated with the 5-mg/kg dose. Common adverse events included arthralgia, back pain, pyrexia, and abdominal pain.² Pyrexia was a serious adverse event in 2 patients.³

References

1. Darbari DS, Sheehan VA, Ballas SK. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management. Eur J Haematol. 2020;105(3):237-246. doi:10.1111/ejh.13430

2. Adakveo. Highlights of prescribing information. Novartis; revised 2021.

3. Blair HA. Crizanlizumab: first approval. Drugs. 2020 Jan;80(1):79-84. doi:10.1007/s40265-019-01254-2

4. Osunkwo I, Manwani D, Kanter J. Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease. Ther Adv Hematol. 2020;11:2040620720955000. doi:10.1177/2040620720955000

5. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439. doi:10.1056/NEJMoa1611770

Reviewed by Harshi Dhingra, MD, on 11/7/2021.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.