Current Landscape in the Pharmacotherapy of Sickle Cell Disease (SCD) - Ernestine Watson Pharm.D.

 Introduction

Sickle cell disease (SCD), the most common monogenic disorder, is a group of inherited red blood cell disorders in which patients inherit two defective hemoglobin genes. In keeping with the National Strategic Plan for the Prevention and Control of Non-Communicable Disease in Jamaica (2013-2018), the Sickle Cell Unit (SCU) located at the Caribbean Institute for Health Research (CAIHR), University of the West Indies (UWI), has placed SCD Newborn Screening as a priority on its research agenda in Jamaica.¹ Between 1973 and 1981 the SCU conducted the Jamaica Sickle Cell Cohort Study, that among other findings, demonstrated that 15% of Jamaican adults are at risk of having a child with SCD and that 1 in every 150 Jamaicans are born with SCD. It is estimated that approximately 18,000 people are living with SCD in Jamaica. Sickle cell disease also has a global impact, affecting approximately 100,000 Americans,² with a high prevalence among people of sub-Saharan Africa, South America, the Caribbean, Central America, Saudi Arabia, India, and the Mediterranean. In this article we will review drugs aimed at preventing the development of complications.

What is sickle cell diseases?

SCD is a chronic haemolytic disorder that is marked by tendency of haemoglobin (Hb) molecules within red cells to polymerise and deform the red cell into a sickle (or crescent) shape resulting in characteristic vasoocclusive events and accelerated haemolysis. It is inherited in an autosomal recessive fashion either in the homozygous state or double heterozygous state. When inherited in the homozygous state, it is termed sickle cell anaemia (SCA). Other known SCD genotypes include haemoglobin SC disease, sickle beta plus thalassaemia, and sickle beta zero thalassemia (which has similar severity with sickle cell anaemia), haemoglobin SD Punjab disease, haemoglobin SO Arab disease, and others.

Complications

Bone Pain Crisis (BPC) is the most consistent and characteristic feature of SCD ⁴. The pain results from activation of nociceptive afferent nerve endings in the ischemic bones. Commonly affected bones include the long bones such as femur and humerus, vertebrae, pelvis, ribs, and sternum. Multiple sites may be involved. Principles of treatment include adequate analgesia, hydration, warmth, prophylactic or therapeutic antibiotics if pyrexial after necessary culture samples are taken, as well as oxygenation if hypoxic (Sp O2 < 90%)

Acute abdominal pain in SCD may be due to sequestration crisis, vaso-occlusion of mesenteric vessels, gall bladder/biliary tract disorders, or other non-SCD specific causes.

Aplastic crisis usually occurs in those less than 16 years of age. It is commonly caused by parvovirus B19 infection which causes transient selective suppression of erythroid progenitors.

Anemia; baseline haemoglobin level in sickle cell disease ranges between 6 and 9 g/dL. In most other patients, significant decline of more than 2 g/dL below steady state level has functional consequences. Untreated severe anaemia is symptomatic and may precipitate heart failure. Causes of worsening anaemia in sickle cell disease may include hyperhaemolysis from any cause, aplastic crisis, megaloblastic crisis, iron deficiency, haemorrhage, renal failure, sequestration crisis, and extreme bone marrow necrosis. Treatment requires both definitive and supportive care.

Cardiovascular disease (CVD) is a significant cause of morbidity and mortality in sickle cell disease.⁵ CVD or stroke refers to a sudden onset focal or global neurologic deficit of vascular origin lasting more than 24 hours. It may be ischaemic or haemorrhagic. Transient Ischemic Attack (TIA) or stroke occurs in 25% of patients with sickle cell disease. Overt stroke occurs in 10 to 15% of homozygous patients under the age of 10 years.

Figure 1. Summaries the changes occurring in the sickled red blood
 cell leading to complications.

Drugs aimed at preventing the development of complications.

Drugs routinely used to treat/manage complications, specifically anemia and vaso-occlusive disease will be reviewed in this article. Drugs used in the prevention and management include Hydroxyurea ⁶, and the more recently approved Volexotor ⁷, L-Glutamine⁸ and Crizanlizumab⁹

Hydroxyurea

Hydroxyurea is an antimetabolite proven to reduce the incidence of vaso-occlusive pain crises and the need for blood transfusions in sickle cell patients. It is also used in adults with sickle cell anemia with recurrent moderate to severe painful crisis. Hydroxyurea slows Hb polymerization. See Figure 2.Decrease in the number of blood cells in the bone marrow may increase the risk of development of a serious infection or bleeding. Hydroxyurea may increase the risk of development of other cancers, including skin cancer.

Although efficacious, hydroxyurea is associated with hematologic and teratogenic toxicities which require frequent monitoring. Hydroxyurea also has an unfavorable side-effect profile, a high rate of nonadherence, and is often under-prescribed by healthcare professionals. The Sickle Cell Unit offers comprehensive monitoring of patients on Hydroxyurea to overcome both the risk of patient non-compliance and adverse effects.

Figure 2. Shows the points where each drug acts to prevent/
slow the development of complications in the patient.

Voxelotor

In 2019, Oxbryta (voxelotor) was approved for the treatment of sickle cell disease in patients aged 12 years or older. Voxelotor is a HbS polymerization inhibitor that blocks the initial step in the production of HbS and works to stabilize oxygenation to reduce sickling of hemoglobin. ⁷ See figure 2.

The HOPE trial evaluated the use of voxelotor versus placebo in sickle cell patients who had a hemoglobin level between 5.5 and 10.5 g/dL and who had experienced one to 10 pain crises within a year. The primary endpoint, an increase in hemoglobin by at least 1 g/dL at week 24, was achieved in 51% of the patients who received voxelotor compared with 7% of the patients who received placebo, regardless of hydroxyurea use (P <.001). Voxelotor also significantly reduced indirect bilirubin (29.08% vs. 3.16%; P <.001) and the percentage of reticulocytes (-19.93% vs. 4.54%; P <.001), which is indicative of its ability to reduce anemia and hemolysis. Voxelotor was also shown to have a greater reduction in the annual incidence of vaso-occlusive pain crisis when compared with placebo. There were no thrombotic events reported during the 24-week trial.¹⁰

Voxelotor is commercially available as an oral formulation that is dosed once daily with or without regard to food. Dose adjustments are required in patients with severe hepatic impairment. There are no contraindications with use; however, patients should be monitored for hypersensitivity reactions. Voxelotor should not be used in pregnant women or in women who are breastfeeding. The most common adverse effects include headache, diarrhea, abdominal pain, nausea, fatigue, rash, and pyrexia.

L-glutamine

In 2017, Endari (L-glutamine) was approved to reduce the frequency of pain crises in sickle cell patients older than age 5 years who experience two or more pain crises a year. L-glutamine is an essential amino acid that reduces oxidative stress in sickled red blood cells by synthesizing nicotinamide adenine dinucleotide (NAD). NAD plays a key role in preventing cell damage in red blood cells, which reduces sickling of hemoglobin and prevents adhesion of red blood cells to endothelium. See figure 2.

L-glutamine was studied in sickle cell patients with or without concomitant use of hydroxyurea in a multicenter, randomized, double-blinded, placebo-controlled, phase III, 48-week study.20 L-glutamine was shown to reduce the frequency of vaso-occlusive pain crises by 25% (3.2 vs. 3.9 events per year; P = .005), and only 8.6% of the patients who received L-glutamine experienced at least one pain crisis within the year following use. L-glutamine was also shown to prolong the duration between the first and second occurrence of pain crises and to reduce the frequency of hospitalizations by 33% (2 vs. 3 mean annual hospitalizations; P = .005). Unfortunately, only 63% of patients who received L-glutamine completed the study protocol; however, only 3.3% of patients discontinued use due to adverse effects.

L-glutamine is commercially available as an oral-powder packet that must be dissolved in 8 ounces of a beverage or eaten with 4 to 6 ounces of food such as applesauce or yogurt. L-glutamine dosing is weight-based and is dosed twice daily. There are no required dose adjustments with use. There are also no reported contraindications with use; however, caution should be used in patients with renal and hepatic impairment. L-glutamine should not be used in pregnant women or in women who are breastfeeding. The most common adverse effects include constipation, headache, and nausea.

Crizanlizumab

Crizanlizumab is a monoclonal antibody that inhibits P-selectin. (9) Vaso-occlusion is caused by the expression of P-selectin, which results in the adhesion of HbS and leukocytes to endothelium. See figure 2. Crizanlizumab was approved in late 2019 to reduce the incidence of vaso-occlusive pain crises in sickle cell patients older than age 16 years who experience frequent pain crises.

In the SUSTAIN trial, crizanlizumab was effective in reducing the incidence of pain crises by 45.3% (P = .01) when compared with placebo, regardless of hydroxyurea use. Better outcomes were observed in patients who were not using hydroxyurea at baseline. More than a third of the patients who received crizanlizumab did not experience a vaso-occlusive crisis, and patients with a reported incidence of five to 10 pain crises at baseline experienced a 63% reduction. Crizanlizumab was also shown to prolong the duration between the first and second occurrence of pain crisis, and it reduced the annual rate of days hospitalized by 41.8%.

Crizanlizumab is the first parenteral agent approved for the management of vaso-occlusive crises. It is a once-monthly IV infusion and requires no dose adjustments with use. There are no reported contraindications with use; however, patients should be monitored for severe infusion-related reactions. Immunogenicity may also occur with use. Crizanlizumab should not be used in pregnant women or in women who are breastfeeding. The most common adverse effects with use are nausea, arthralgia, back pain, and pyrexia. Table 1 summaries information on the four drugs discussed above.

Table 1. Summary of Drugs on the SCD Landscape

Drug/ Year of FDA approval	Target	MOA	Hb	Pain	Benefits	Disadvantage
Hydroxyurea 1998	Decrease Polymerization	Heterocellular Increase HbF	yes	yes	PO once daily dosing, inexpensive	Requires consistent monitoring to achieve outcomes
L-glutamine 2017	RBC redox	Decrease RBC oxidative stress	yes	yes	PO, Fairly inexpensive	Taste, non-compliance
Crizanlizumab 2019	vasculopathy	P selectin mAb	no	yes	Monthly dosing	IV, Very expensive
Voxelotor 2019	Decrease Polymerization	Increase oxygen affinity	yes	no	PO	Very expensive

Conclusion

Hydroxurea maintains a particularly important position in the arsenal of drugs used to prevent the development of complications among SCD patients. The Sickle Cell Unit at the Caribbean Institute Health Research continues to lead the way in assisting patients to achieve and maintain control by providing services to SCD patients on Hydroxyurea who may discontinue treatment due to adverse reactions while on the therapy.

The newer entrants L-glutamine, Volexetor and Crizanlizumab were approved by the FDA between 2017 and 2019. They act at various points to help individuals who may not be able to tolerate or are unresponsive to Hydroxyurea to gain better control and in so doing prevent complications associated with the disease.

This review focused on drug therapy, however therapies such as Stem Cell transplant and Gene therapy also offer significant opportunities for advancement in the overall treatment of SCD. They all improve life expectancy and quality of life experienced by these patients and offer hope for future developments.

 References

1. The Sickle Cell Unit (SCU) Caribbean Institute for Health Research https://uwi.edu/caihr/about/pg-scu.php.   Accessed June 17, 2021
2. CDC. Data and statistics on sickle cell disease. www.cdc.gov/ncbddd/sicklecell/data.html.  Accessed June 18, 2021
3. World Health Organisation, “Management of haemoglobin disorders,” in Proceedings of the Report of Joint WHO-TIF Meeting, Nicosia, Cyprus, November 2007. View at: https://apps.who.int/iris/bitstream/handle/10665/43969/9789241597128_eng.pdf
4. O. S. Platt, B. D. Thorington, D. J. Brambilla et al., “Pain in sickle cell disease: rates and risk factors,” The New England Journal of Medicine, vol. 325, no. 1, pp. 11–16, 1991. https://www.nejm.org/doi/full/10.1056/NEJM199107043250103 Accessed 17/06/2021 
5. M. A. Ware, I. Hambleton, I. Ochaya, and G. Serjeant, “Day-care management of sickle cell painful crisis in Jamaica: a model applicable elsewhere?” British Journal of Haematology, vol. 104, no. 1, pp. 93–96, 1999. https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2141.1999.01160.x  Accessed June 15, 2021
6. Droxia (hydroxyurea) prescribing information. Princeton, New Jersey: Bristol-Myers Squibb Company; 2019.
7. Voxelotor monograph for professionals. https://www.drugs.com/drug-interactions/voxelotor.html  Accessed June 15, 2021
8. Endari (L-glutamine) prescribing information. Torrance, CA: Emmaus Medical, Inc; 2017.
9. Adakveo (crizanlizumab) prescribing information. East Hanover, NJ: Novartis; 2019.
10. Vichinsky E, Hoppe C, Atoga K, et al. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519.