STAND Trial: Crizanlizumab Shows No Superiority Over Placebo for Sickle Cell Disease

Miguel R. Abboud, MD

Credit: American University of Beirut Medical Center

Crizanlizumab 5 mg/kg and 7.5 mg/kg did not demonstrate superiority over placebo on key primary and secondary efficacy endpoints among patients aged ≥12 years with sickle cell disease (SCD) in the phase 3 STAND study, according to new results.¹

Crizanlizumab, a selective, humanized immunoglobulin G2 kappa anti–P-selectin monoclonal antibody, previously showed positive clinical activity and tolerability in patients with SCD aged ≥16 years in the SUSTAIN trial compared to placebo.

Results from STAND showed no statistically significant differences in the annualized rates of vaso-occlusive crises (VOCs), or pain crises, leading to healthcare visits, or those managed at home, between crizanlizumab 5 & 7.5 mg/kg and placebo among patients with SCD.

“These results differ from the previous study results and may be due to various factors, such as geographic differences in healthcare utilization as well as the low VOC rates in all arms, possibly either due to selection of patients with less severe disease, or, more likely due to the lower reporting of VOCs during the pandemic,” wrote the investigative team, led by Miguel R Abboud, MD, department of pediatrics and adolescent medicine, American University of Beirut Medical Center.

The STAND study was conducted at 65 study sites in 21 countries, with a data cutoff in August 2022. Those aged ≥12 years with a history of ≥2 vaso-occlusive crises (VOCs) and with or without concomitant treatment with hydroxyurea or hydroxycarbamide were randomized to receive intravenous crizalnizumab 5mg/kg, 7.5mg/kg, or placebo. Investigators evaluated adverse events and levels of biomarkers including soluble P-selectin (sPsel).

Overall, the trial enrolled 252 patients aged ≥12 years with SCD: 85 received placebo, 84 received crizanlizumab 5mg/kg, and 83 patients received crizanlizumab 7.5 mg/kg, respectively. The mean age of patients was 27.8 years, 54 (21.4%) were adolescents, and 139 (55.2%) were female. Treatment was discontinued in 27 (31.8%), 18 (21.4%), and 15 (18.1%) patients in the placebo, crizanlizumab 5 mg/kg, and 7.5 mg/kg arms, respectively, due to patient and physician decision.

Upon analysis, results from STAND showed no statistically significant difference in the adjusted annualized rates of VOCs leading to healthcare visits between crizanlizumab 5 and 7.5 mg/kg (RR, 1.08 [95% CI, 0.76 - 1.55]; P >.999) and placebo (RR, 0.89 [95% CI, 0.62 - 1.27]; P >.999). The adjusted annualized rates of VOCs managed at home and/or leading to a healthcare visit also showed no statistically significant difference between crizanlizumab 5 & 7.5 mg/kg (1.21; 95% CI, 0.87 - 1.70) and placebo (0.83; 95% CI, 0.59 - 1.17).

Safety results were consistent with the known safety profile of crizanlizumab use among patients with SCD and suggested no new safety concerns. Adverse events were reported in 77 (90.6%), 74 (88.1%), and 77 (92.8%) patients with placebo, crizanlizumab 5mg/kg, and crizanlizumab 7.5 mg/kg, respectively. The most common were pyrexia (22 [25.9%], 22 [26.2%], 19 [22.9%]), COVID-19 (17 [20.0%], 18 [21.4%], 27 [32.5%]), and headache (16 [18.8%], 21 [25.0%], 13 [15.7%]).

Each crizanlizumab treatment arm indicated a reduction in free soluble P-selectin (sPsel) compared to placebo, suggesting the effect of crizanlizumab on the biomarker level. At week 3, day 1, free sPsel showed a relative change from baseline in the geometric mean of 1.01 with placebo versus 0.05 and 0.06 with 5 mg/kg and 7.5 mg/kg doses of crizanlizumab, respectively.

“Relative change from baseline in total sPsel remained close to 0% in the placebo arm at different study visits, while it increased in treatment arms from week 3 Day 1 onward, plateauing at week 15 Day 1,” investigators wrote.

References

_{Abboud MR, Cançado RD, De Montalembert M, Smith WR, Rimawi H, et. al. Efficacy, Safety, and Biomarker Analysis of 5 Mg and 7.5 Mg Doses of Crizanlizumab in Patients with Sickle Cell Disease: Primary Analyses from the Phase III STAND Study. Paper presented at 2023 American Society of Hematology (ASH) Annual Meeting in San Diego, California. December 9 - 12, 2023.}