Sickle cell disease (SCD) is an autosomal recessive, monogenic disorder associated with early age morbidity and mortality. Both of which are related to acute and chronic disease-associated complications (1). SCD comprises a group of disorders caused by two beta (β)-globin gene (HBB) pathogenic variants, of which at least one is the characteristic substitution of glutamic acid for valine at residue 6 on the β-chain of adult hemoglobin (HbA), resulting in sickle cell hemoglobin (HbS) production (2). HbS polymerization upon deoxygenation is considered central to the disease pathology, contributing to hemolysis with chronic anemia and recurrent vaso-occlusive crises (VOCs) with ischemia-reperfusion injury, in addition to chronic endothelial dysfunction and sterile inflammation, resulting in a viscous cycle (3).

On November 15, 2019, the dual functional, first-in-class humanized immunoglobulin G2 (IgG2)-kappa, anti-P-selectin monoclonal antibody crizanlizumab (Adakveo^®) was first approved by the US Food and Drug Administration (FDA) (4, 5). Crizanlizumab was indicated to reduce the frequency of VOCs in older adolescent and adult patients, aged 16 years (yrs) and older suffering from SCD. The approval was based on the positive results observed in the phase 2, double-blind, randomized, placebo-controlled SUSTAIN Trial (NCT01895361) (6–11). In the per-protocol population (N=125), defined as patients who underwent randomization, and who received at least 12 of the 14 scheduled crizanlizumab doses (5.0 mg/kg body weight (BW)), a 52.3% reduction in the annual VOC rate was observed (median, 1.04 vs 2.18 crises per year; p=0.02) (12). In this study, the overall benefit of crizanlizumab was irrespective of concomitant hydroxycarbamide (HC) therapy and/or past VOCs, and incidences of adverse events (AEs) and serious adverse events (SAEs) were similar among patients treated with crizanlizumab and placebo-treated patients (11–13).

On July 23, 2020, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for crizanlizumab, resulting in a conditional marketing authorization valid in Europe on October 28, 2020 (11). In Europe, crizanlizumab was indicated for the prevention of recurrent VOCs in SCD patients ≥16 yrs of age at a dose of 5.0 mg/kg BW, given either as an add-on therapy to HC or as a monotherapy in patients in whom the use of HC was inappropriate or inadequate. However, data obtained from the confirmatory STAND Trial (CSEG101A2301; NCT03814746) were requested by the EMA as part of the conditions for approval (11).

On May 26, 2023, the CHMP recommended to revoke the conditional marketing authorization for crizanlizumab in the European Union (EU) (14). This recommendation was based on the preliminary results of the STAND Trial, as no difference between crizanlizumab (5.0 mg/kg BW) (2.49; 95% confidence interval (CI) [1.90; 3.26]) and placebo (2.30; 95% CI [1.75; 3.01]) in the annual VOC rate leading to a physician visit in the first year following randomization (primary endpoint) was observed (rate ratio 1.08; 95% CI [0.76; 1.55]). The adjusted annual rate, estimated by negative binomial regression, for VOCs that resulted in a physician visit and were treated at home (main secondary endpoint) was 4.70; 95% CI [3,60; 6,14] in the crizanlizumab 5.0 mg/kg arm versus (vs) 3.87; 95% CI [3,00; 5,01] in the placebo arm (rate ratio 1.21, 95% CI [0,87; 1,70]). In crizanlizumab-treated patients’, higher rates of grade ≥3 treatment-related adverse events (TAEs) were further reported; however, no new safety concerns were raised (14, 15).

Therefore, the conditional marketing authorization for crizanlizumab in the EU was revoked on May 26, 2023 (Article 20 of Regulation European Commission (EC) No 726/2004), in consultation with the EMA and the Paul Ehrlich Institute (PEI) as the risk-benefit ratio could no longer be considered positive (14, 15).

From December 2020 to December 2022, 11 patients consented to treatment with crizanlizumab (age (median) 29 yrs, range 19 to 42 yrs; homozygous sickle cell disease (HbS/S) 54.5% (6/11)). The annual VOC rate (both, uncomplicated and complicated VOCs) prior to crizanlizumab induction was 2 (median), range 1 to 11. In total, three patients were excluded from data analysis, of which 2 (both, HbS/S) did not receive ≥2 crizanlizumab infusions as they were lost to follow-up due to change of residence. The third patient (sickle beta (β)-thalassemia, HbS/β) who was excluded from evaluation according to study definitions, suffered from ≥10 opioid-dependent VOCs/yr, requiring both, partial manual exchange transfusions every 4 wks in addition to HC (MTD 25 mg/kg BW) for ≥12 months prior to crizanlizumab induction.

In total, 8 patients were eligible for evaluation, of which 7 patients [age (median) 29 yrs, range 25 to 42 yrs; HbS/S 57.1% (4/7)] received ≥2 crizanlizumab infusions, as in one sickle hemoglobin C disease (HbS/C) patient treatment discontinuation was secondary to an infusion-related VOC requiring inpatient admission. In the remaining 7 crizanlizumab-treated patients, median observation time was 17.5 months, range 4.8 to 27.3, with a median number of 12 crizanlizumab infusions (range 5 to 26) being infused. During follow-up, patients were adherent to treatment, resulting in no substantial delay over time. Patients’ baseline characteristics are presented in Table 1. Both patient groups were well balanced [i.e., annual VOC rates prior to treatment in the crizanlizumab group was 3, range 1 to 5, likewise to HC-treated patients (3, range 1 to 4)].

SCD is considered a rare disease in Germany with an estimated number of at least 2.000 affected patients (17). Besides the monocentric character of the present analysis with a resulting low number of crizanlizumab-treated patients at AHO at the University Hospital of Essen and no placebo-matched control group, our data support the preliminary findings observed within in the STAND Trial (18), resulting in no significant benefit of crizanlizumab in reducing (annual) VOCs rates in addition to a high rate of (S)AEs in these patients. Furthermore, standard HC therapy at a MTD proved to be superior to crizanlizumab-monotherapy in the studied patients.

(Minor) differences were applied for the definition of VOCs in contrast to both crizanlizumab studies. In the present analysis add-on therapy with HC, including subsequent dose titration, and voxelotor was allowed throughout observation time. These therapeutic attempts represent what we consider to be more accurate in daily practice.

In the SUSTAIN Study a -32.1% lower rate in the median crisis rate/yr was observed in patients receiving HC and crizanlizumab (13). Unfortunately, none of the patients treated in the present analysis did consent to prior HC treatment despite experiencing high rates of VOCs that required frequent hospitalizations. Therefore, a (potentially) synergistic effect cannot be excluded. During follow-up, however, two crizanlizumab-treated patients consented to add-on HC therapy, as no reduction in VOCs was observed. Add-on therapy with HC in these patients, likewise to the HC-control group, was well tolerated during follow-up (on average 10 months), resulting in an overall improvement of patients’ daily physical activities with no need for VOC-related in-patient admissions at data cut-off.

To date, no HC dosing data (mg/kg BW) are reported in both crizanlizumab studies (SUSTAIN and STAND). This, together with the fact, that a HC dose titration was excluded, will further not answer the question of a (potentially) synergistic effect at a HC-MTD pattern. Furthermore, no data supporting the adherence of patients to HC can be drawn from these two trials in our opinion. Considering the divergent results observed within these studies, in addition to the data observed within the present analysis, a (partial) poor adherence to HC in patients treated within the STAND Trial might potentially be assumed. Although the selected control group within this present analysis might represent a comparative group of only limited significance, this comparison allows to highlight the efficacy of HC in patients with good adherence to HC at a MTD in comparison to crizanlizumab monotherapy.

These findings, together with the overall high economic burden of crizanlizumab treatment ranging between $7,071 to $9,428/month ($84,852 and $113,135/year) in contrast to the cost-effectiveness of HC monotherapy, does further support EMA’s decision in our opinion to revoke the conditional approval of crizanlizumab in Europe (19–23). Following the withdrawal of the marketing authorization for crizanlizumab in Europe, the question of further therapeutic options (cell-based gene therapies excluded) for patients who have benefited from a crizanlizumab-based therapy remains unanswered, as it is obvious that most of these patients will have already refused therapy with HC (24). Regarding ongoing trial data assessment, physicians outside Europe should consider the potential risks when making a therapeutic decision regarding the use of crizanlizumab.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Ethics Committee of the University of Duisburg-Essen (23-11246-BO). The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

FP: Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft. AR: Formal analysis, Validation, Writing – review & editing. RY: Formal analysis, Methodology, Validation, Writing – review & editing. HCR: Formal analysis, Validation, Writing – review & editing. FA: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.