Approved Sickle Cell Drug Fails to Beat Placebo in Trial

Crizanlizumab (Adakveo) failed to outperform placebo in patients with sickle cell disease, the phase III STAND trial showed.

Adjusted annualized rate of vaso-occlusive crises leading to healthcare visits was 2.49 with the standard 5-mg/kg dose of the monoclonal antibody and 2.04 with a 7.5-mg/kg dose, neither of which were significantly different than the annualized rate of 2.30 with placebo:

• Standard crizanlizumab dose: rate ratio (RR) 1.08 (95% CI 0.76-1.55)
• Higher dose: RR 0.89 (95% CI 0.62-1.27)

Moreover, there was no significant difference for crises managed at home leading to healthcare visits, with adjusted annualized rates of 4.70 in the standard-dose group, 3.22 in the higher-dose group, and 3.87 in the placebo group, reported Miguel R. Abboud, MD, of the American University of Beirut Medical Center in Lebanon, and colleagues in Lancet Haematology.

“The safety results were consistent with the known safety profile of crizanlizumab in patients with sickle cell disease, with no new safety concerns,” they wrote.

Abboud’s group pointed out that the results of the STAND trial were at odds with the phase II SUSTAIN trial, which showed a 45.3% reduction in the rate of vaso-occlusive crises per year and a longer median time to the first crisis with crizanlizumab 5 mg/kg compared with placebo, irrespective of hydroxyurea use and sickle cell genotype. SUSTAIN was the basis for FDA approval and European Medicines Agency (EMA) approval for crizanlizumab for the prevention of vaso-occlusive crises in patients ages 16 years and older with sickle cell disease.

STAND’s results led the EMA to revoke the conditional marketing authorization for crizanlizumab, while it remains approved for use by the FDA.

In a commentary accompanying the study, Sebastian Mendez-Marti, MD, and Swee Lay Thein, DSc, both of the Sickle Cell Branch of the National Heart, Lung, and Blood Institute, said the difference in trial results between STAND and SUSTAIN could be due to several reasons.

For example, they pointed out that the placebo group in STAND had lower rates of vaso-occlusive crises than in SUSTAIN. Furthermore, they suggested that behavior changes during the COVID-19 pandemic that discouraged medical care access could have affected the results in the STAND trial.

“Although crizanlizumab shows potential in managing sickle cell disease-related complications, its role remains uncertain, and further research is needed to clarify its efficacy and identify the patient population that might benefit most,” they wrote.

Abboud and colleagues noted that “these findings underscore the nuanced interplay among environmental and genetic factors, trial settings, patient demographics, and healthcare use and their influence on treatment efficacy and patient outcomes.”

“Definitive conclusions regarding the benefit of crizanlizumab treatment await future clinical trials, to continue developing the body of evidence on crizanlizumab for timely sickle cell disease treatment and global patient access,” they concluded.

STAND included patients ages 12 years and older with sickle cell disease across 65 sites in 21 countries. Between July 2019 and August 2022, 252 patients were randomly assigned (1:1:1) to receive 5 mg/kg of crizanlizumab, 7.5 mg/kg of crizanlizumab, or placebo, in addition to standard of care (including hydroxyurea) for 1 year.

At the time of data cutoff, 76% of patients were enrolled in the study and were on treatment. More patients discontinued placebo (n=27) than crizanlizumab (n=18 in the standard-dose group and n=15 in the higher-dose group).

The safety profile of crizanlizumab was in line with previous findings, with pyrexia, headache, and nausea being commonly reported adverse events.

Grade 3 or higher adverse events were less frequent in the placebo and crizanlizumab 7.5 mg/kg groups than in the 5 mg/kg group (32% and 39% vs 56%). Serious adverse events (all grades) were also less frequent (31% and 27% vs 42%, respectively).

Infusion-related reactions were reported in 37% of patients in the crizanlizumab 5 mg/kg group, 40% in the 7.5 mg/kg group, and 29% in the placebo group.

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