Crizanlizumab fails to demonstrate benefit over placebo in patients with sickle cell disease

The phase III STAND study compared the efficacy and safety of crizanlizumab (5 and 7.5 mg/kg) vs. placebo in patients with sickle cell disease of at least 12 years old. In contrast to previous results from the phase II SUSTAIN study, the STAND study could not demonstrate superiority with crizanlizumab over placebo on its primary and secondary efficacy endpoints.

Crizanlizumab is a humanised monoclonal antibody directed against P-selectin, a key driver of cellular adhesions that lead to vaso-occlusive crises (VOCs). In the phase II SUSTAIN study, crizanlizumab (5 mg/kg) reduced the annualised rate of VOCs leading to a healthcare visit by 45.3% as compared to placebo, and showed general tolerability in sickle cell disease (SCD) patients aged ≥16 years. The phase III STAND study was designed to confirm the efficacy and safety of the crizanlizumab 5 mg/kg dose and to assess the safety and efficacy of 7.5 mg/kg dose in patients with SCD aged ≥ 12 years.

Study design

STAND is an ongoing, multicentre, randomised, double-blind, placebo-controlled phase III trial that enrolled sickle cell disease patients aged ≥12 years with a history of vaso-occlusive crises (VOCs), with or without concomitant treatment with hydroxyurea/hydroxycarbamide. Patients were randomised 1:1:1 to intravenous treatment with crizanlizumab 5 mg/kg, crizanlizumab 7.5 mg/kg or placebo (on days 1 and 15 and every 4 weeks thereafter) in addition to standard of care therapy. The primary endpoint was the annual frequency of VOCs leading to a healthcare visit. Adverse events (AEs) were evaluated based on MedDRA version 25.1 and severity on CTCAE v5.0. Levels of biomarkers such as soluble P-selectin (sPsel), were evaluated.

Results

In total, 252 patients were randomised and treated with crizanlizumab 5 mg/kg (N= 84), crizanlizumab 7.5 mg/kg (N= 83) or placebo (N= 85). Median age of the patients was 25.0 years, 55.2% were female and most patients (72.6%) received prior treatment with hydroxyurea/hydroxycarbamide. Over the past 12 months, patients experienced a mean of 3.8 VOCs.

No statistically significant difference was found in the primary endpoint of annual frequency of VOCs leading to a healthcare visit between the crizanlizumab 5 mg/kg group and the placebo group (2.49 vs. 2.30; RR[95%CI]: 1.08 [0.76-1.55]) and between the crizanlizumab 7.5 mg/kg group and the placebo group (2.04 vs. 2.30; RR[95%CI]: 0.89[0.62-1.27]). Furthermore, no statistically significant difference was found in the annual frequency of VOCs that led to a healthcare visit and/or could be managed at home between the crizanlizumab 5 mg/kg group and the placebo group (4.70 vs. 3.87; RR [95%CI]: 1.21[0.87-1.70]) and between the crizanlizumab 7.5 mg/kg group and the placebo group (3.22 vs. 3.87; RR[95%CI]: 0.83[0.59-1.17]). Adverse events (AEs) were reported by 88.1% of patients in the crizanlizumab 5 mg/kg group, 92.8% of patients in the crizanlizumab 7.5 mg/kg group and 90.6% of patients in the placebo group. The most common AEs were pyrexia (25.9%, 26.2% and 22.9% respectively), COVID-19 (20.0%, 21.4% and 32.5% respectively) and headache (18.0%, 21.4% and 32.5% respectively). Serious adverse events (SAEs) and grade ≥3 AEs occurred more frequently in the crizanlizumab 5 mg/kg group (41.7% and 56.0%, respectively) than in the crizanlizumab 7.5 mg/kg group (26.5% and 38.6% respectively) and the placebo group (30.6% and 31.8% respectively). Treatment-related SAEs and AEs leading to treatment discontinuation were rare (<4% in all groups). None of the six fatal SAEs, two in each group, were related to treatment.

At week 3, day 1, levels of free P-selectin showed a relative change from baseline in geometric mean (CV%, range) of 1.01 (56.2, 0.201-7.37) with placebo vs. 0.05 (88.9, 0.00507-0.225) and 0.06 (68.4, 0.0146-0.208) with crizanlizumab at 5 and 7.5 mg/kg doses, respectively.

Major differences between the STAND and SUSTAIN studies include the occurrence of the COVID-19 pandemic with its effects on healthcare, patient behaviour and triggers of VOCs accentuated by the geographical dispersion of patients. These differences may have contributed to the differing efficacy results.

Conclusion

In contrast to the results of the phase II SUSTAIN trial, the primary analyses of the phase III STAND trial could not demonstrate superiority of crizanlizumab (5 or 7.5 mg/kg) over placebo. The safety results were consistent with the known safety profile of crizanlizumab in SCD patients, with no new safety concerns. Both crizanlizumab arms demonstrated reductions in free soluble P-selectin versus placebo, demonstrating crizanlizumab activity.

Reference

Abboud MR, 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. Presented at ASH 2023; Abstract 272.