For the First Time, a Drug Receives FDA Approval to Treat Sickle Cell Anemia!

On 15 November 2019, the US Food and Drug Administration (FDA), sickle cell anemia in adults and children aged 16 years and older, was the condition for which vaso-occlusive (blood vessel-blocking) crises were targeted: the agency approved the monoclonal antibody drug crizanlizumab-tmca (Adakveo) to reduce their frequency.

A 52-week, randomized, multicenter, placebo -controlled, double-blind clinical trial , SUSTAIN, evaluated efficacy in 198 patients with sickle cell disease. Patients received an intravenous infusion over 30 minutes of crizanlizumab-tmca 5 mg/kg (67 patients), crizanlizumab-tmca 2.5 mg/kg (66 patients) or placebo (65 patients), randomized into 3 arms. Administration took place at weeks 0 and 2 and every 4 weeks thereafter. Randomization was stratified according to prior hydroxyurea use (yes or no) and the number of vaso-occlusive crises in the preceding 12 months.

The study’s primary efficacy outcome was the median annual rate of acute vaso-occlusive crises (VOK) leading to a hospital visit.

In patients receiving 5 mg/kg crizanlizumab-tmca, the median annual VOK rate was lower than with placebo (1.63 versus 2.98). Reduced VOK frequency was observed regardless of sickle cell disease genotype and/or hydroxyurea use. Among patients treated with crizanlizumab-tmca 5 mg/kg, 36% were reported to have no VOK, compared with 17% in the placebo arm. Median time from study entry to the first anemia crisis with crizanlizumab-tmca 5mg/kg versus placebo was 4.1 versus 1.4 months, respectively.

The most common (>10%) side effects in patients receiving crizanlizumab-tmca were nausea, arthralgia, back pain and pyrexia (fever).

The recommended doseis administered at weeks 0 and 2, then every 4 weeks, over 30 minutes intravenously, at 5 mg/kg.

What is sickle cell anemia?

Sickle cell anemia is characterized by hemolysis (breakdown of blood cells) and vaso-occlusion and is the most common inherited erythrocyte (red blood cell) disease. Sickling of erythrocytes causes capillary-level blockage and hence reduced blood flow to tissues, resulting in infarction, chronic hemolysis, chronic inflammation and organ dysfunction. Acute and chronic manifestations increase with age, and these complications cause premature death. OHA management requires a detailed, multidisciplinary approach in both pediatric and adult patients. For prevention of recurrent vaso-occlusive crises, until crizanlizumab-tmca', hydroxyurea was the only treatment option used. Chronic blood transfusion has been shown effective in preventing primary and secondary stroke risk and recurrent acute chest syndrome. Infections are the leading cause of death in pediatric patients, making penicillin prophylaxis and appropriate vaccination protocols, particularly against encapsulated bacteria, vital. Hematopoietic stem cell transplantation is the only known curative treatment, with an 85-90% success rate in selected high-risk pediatric patients.

How Does Crizanlizumab-tmca Work?

Crizanlizumab is a monoclonal antibody developed by Novartis that targets the cell-surface molecule P-selectin. P-selectin is abundant on platelets and epithelial cells in the endothelial layer lining the inner walls of blood vessels. By binding P-selectin, crizanlizumab prevents blood cells and sickled erythrocytes from adhering to endothelial cells.

Video: Crizanlizumab-tmca Mechanism of Action and the SUSTAIN Study