By Iulia Kis
Sickle cell disease (SCD) is the most common inherited blood-related disease, presenting in an estimated 20-25 million people.1 SCD significantly reduces the quality of life of affected patients due to its characteristic presence of sickle haemoglobin (HbS) leading to conditions such as vaso-occlusive crises (crises related to SCD-related pain), organ dysfunction and early death. The symptom accounting for most patient-healthcare professional encounters, from those already suffering from SCD, are vaso-occlusive crises (VOC) 2 caused primarily by the polymerization of HbS. This causes the adhesion of erythrocytes and activated leukocytes to the activated endothelium, thus forming aggregates that hinder blood flow and can often include monocytes, platelets and neutrophils, with leukocytes being the main culprit. The events that follow leukocyte adhesion are dependent on P-selectin, which plays an important role in the activation of platelets, coagulation, inflammation.3 However, VOC can now be alleviated by the newly approved Novartis drug, Adakveo.
Over the last two decades, there has been little change in the treatments prescribed for SCD patients in the United Kingdom. The main treatment is Hydroxyurea, which is used in both children and adults as it reduces the severity of SCD related complications. The effects of Hydroxyurea consist of increasing the baseline total Hb concentration and are best achieved when the dose administered is the maximum tolerated dose.4 Another commonly used treatment is glutamine which prevents oxidative damage to red blood cells. This results in a small, but clinically significant reduction in the number of acute SCD patient crises as well as SCD-related hospitalisation needs. Unfortunately, there is a lack of knowledge about the optimal dose of glutamine.4 For serious SCD complications, such as stroke, acute chest syndrome and splenic sequestration, transfusion therapy is often considered as a potential treatment.4
In November 2019, a new medicine, Adakveo (by Novartis) was approved by the United States Food and Drug Administration to reduce the frequency of pain crises and hospitalisations for patients suffering from SCD.5 The active substance in Adakveo is crizanlizumab and its approval was based on the extensive SUSTAIN study that proved its efficacy. The drug was finally approved by the National Health Service in the UK in October 2021 and is currently awaiting final guidance from the National Institute for Health and Care Excellence.6 To understand the importance of this decision and the extent to which it benefits SCD patients in the UK, an in depth dive into the research behind crizanlizumab, its structure and mechanism of working is crucial.
Adakveo targets the upregulation of P-selectin expression in the vascular endothelium after sickled red blood cells (RBC) have adhered to it. Crizanlizumab is a humanized monoclonal antibody that creates a P-selectin blockade, stopping the sickled RBCs from adhering to the endothelium. The SUSTAIN study was performed in 2017 and included 198 patients, of which only 129 completed the study, randomised at 60 different sites. The participants were split into three groups: receiving a placebo, crizanlizumab in a low dose (2.5mg/kg of body weight), or crizanlizumab at a high dose (5.0mg/kg body weight). In all three groups, patients that were or were not administered Hydroxyurea concurrently to the study were included and either crizanlizumab or the placebo were first administered in a loading dose, 2 weeks apart, followed by maintenance doses every 4 weeks for a year. 7
The primary aim of the study was to determine the median crisis rate per year alongside the time between crises. The results of the study showed no significant differences in these outcomes between the placebo and low-dose groups, but there were significant differences between the placebo and high-dose groups.7 The median crisis rate per year was 2.98 for the placebo group, compared to 1.63 for the high-dose group. In both groups, a similar percentage of participants were also administered hydroxyurea concomitantly (62% for placebo and 63% for high-dose receivers). The time to the first crisis since the start of the study was 4.07 months in the high-dose group and only 1.38 months in the placebo group, and the time to second crisis was twice as high in the high-dose group (10.32 months) compared to the placebo group (5.09 months).7 The study was questioned on the basis that the difference in annual crisis rate was much higher between patients not receiving hydroxyurea than those receiving it, pointing to the fact that these two drugs did not act synergistically.8 However, this did not disprove crizanlizumab’s effectiveness, as there was no biological basis on which the drugs were expected to act together, and, overall, patients that receive hydroxyurea have been shown to have more annual crises.8 Furthermore, a later analysis of results from the SUSTAIN study in patient subgroups further confirmed the drug’s efficacy. The same data obtained from the 2017 study was used to determine that even patients that had 5-10 VOC in the year before the study commenced, those that used hydroxyurea and the patients with the most severe HbSS genotype benefitted from crizanlizumab use.9
This newly approved drug aims to improve many lives, along with future therapies that are now under development. One such drug, Voxelotor, has already been analysed in a phase 3 clinical trial. It acts by inhibiting the polymerization of HbS, thus significantly increases the basal Hb level and decreases haemolysis.10 The multitude of medicines currently undergoing testing ensure Sickle Cell Disease patients will not have to go another two decades before the next effective treatment is made available to them.
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2. Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. American Journal of Hematology. John Wiley & Sons, Ltd; 2005;79(1): 17–25. Available from: doi:10.1002/AJH.20336 [Accessed: 12th October 2021]
3. Man Y, Goreke U, Kucukal E, Hill A, An R, Liu S, et al. Leukocyte adhesion to P-selectin and the inhibitory role of Crizanlizumab in sickle cell disease: a standardized microfluidic assessment. Blood cells, molecules & diseases. NIH Public Access; 2020;83: 102424. Available from: doi:10.1016/J.BCMD.2020.102424 [Accessed: 11th October 2021]
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5. New Novartis medicine Adakveo® (crizanlizumab) approved by FDA to reduce frequency of pain crises in individuals living with sickle cell disease | Novartis. [Online] Available from: https://www.novartis.com/news/media-releases/new-novartis-medicine-adakveo-crizanlizumab-approved-fda-reduce-frequency-pain-crises-individuals-living-sickle-cell-disease [Accessed: 11th October 2021]
6. NHS England » NHS announces deal for life changing sickle cell treatment. [Online] Available from: https://www.england.nhs.uk/2021/10/nhs-announces-deal-for-life-changing-sickle-cell-treatment/ [Accessed: 11th October 2021]
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8. Zhou Yu, M.D., Ph.D. LeAnn Blankenship, M.D. Ishmael Jaiyesimi DO. Crizanlizumab in Sickle Cell Disease. https://doi.org/10.1056/NEJMc1703162. Massachusetts Medical Society; 2017;376(18): 1795–1796. Available from: doi:10.1056/NEJMC1703162 [Accessed: 12th October 2021]
9. Kutlar A, Kanter J, Liles DK, Alvarez OA, Cançado RD, Friedrisch JR, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. American Journal of Hematology. John Wiley & Sons, Ltd; 2019;94(1): 55–61. Available from: doi:10.1002/AJH.25308 [Accessed: 11th October 2021]
10. Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El-Beshlawy A, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. https://doi.org/10.1056/NEJMoa1903212. Massachusetts Medical Society; 2019;381(6): 509–519. Available from: doi:10.1056/NEJMOA1903212 [Accessed: 12th October 2021]