Oxbryta (voxelotor) and Adakveo (crizanlizumab) are targeted therapies for Sickle Cell Disease
Sickle Cell Disease (SCD) is a genetic disease affecting red blood cells (RBCs) and decreases life expectancy by about 30 years. Many companies are working to develop therapeutics for SCD. Oxbryta (voxelotor) and Adakveo (crizanlizumab) were approved recently to treat SCD. These drugs target molecular interaction and are effective clinically. A number of other therapeutic options are currently being evaluated to treat/cure SCD.
Sickle Cell Disease decreases life expectancy by about 30 years
SCD is a monogenic disease in which a nucleobase substitution in the β-globin gene produces a sickle hemoglobin (HbS). HbS causes red blood cells to become stiff, abnormally shaped and stick together resulting in decreased oxygenation. At a systemic level, HbS and decreased oxygenation to RBCs manifest as hemolysis, chronic anemia, inflammation and vaso-occlusion leading to tissue hypoxia and multi-organ failure. Systemic complications, particularly vaso-occlusive crises result in frequent hospital visits and multi-organ failure and other complications lead to death (Figure 1).1,2
Figure 1: Molecular level changes to clinical outcomes of sickle cell disease
The three most common types of SCD are Sickle Cell Anemia (SS), Sickle Hemoglobin-C disease (SC), Sickle Beta-Plus Thalassemia and Sickle Beta-Zero Thalassemia.
SCD affects about 100,000 people in the U.S. and has an incidence rate of 1 in 365 births in the African-American babies and 1 in 16,300 Hispanic-American births. SCD decreases life expectancy by about 30 years.1,2
Oxbryta and Adakveo target key SCD pathways and increase oxygenation to RBCs
SCD is currently treated by blood transfusions, hydroxyurea opioids to treat vaso-occlusive crises. Endari (L-glutamine) (Figure 2) was approved by FDA in 2017 for SCD. Its mechanism is not completely understood, but as an antioxidant it decreases the oxidation of cells and causes reduced the tissue or organ damage.3
Oxbryta (voxelotor) (Figure 2) is a small-molecule inhibitor that binds to the mutated valine residue on the α-chain of hemoglobin. The aldehyde on Oxbryta forms a Schiff-base with the valine and prevents it from polymerizing HbS, increases oxygenation to RBCs and prevents tissue/organ damage.1,4
Adakveo (crizanlizumab) (Figure 2) is a mono-clonal antibody that binds to P-selectin, a key protein responsible for aggregation of cells. This binding leads to increased oxygenation to cells, thereby reducing the risk of organ damage due to oxygen insufficiency.5
Figure 2: Structure of Endari, Oxbryta, and Adakveo (representative monoclonal antibody)
Oxbryta is priced at $125,000 per patient per year
The current national disease burden due to SCD is estimated to be about $3 billion (as of 2015). The disease management expenses indicate a significant financial burden with inpatient, outpatient and out-of-pocket expenses at $15,040, $10,079 and $1,273 per patient per year, respectively.6
Vaso-occlusive crises decreased significantly in patients (Table 1) who were administered Adakveo and Oxbryta compared to Endari, indicating that targeted therapies are more effective in treating patients. As expected, these targeted therapies are also priced at a premium.
Table 1: List of SCD approved drugs and clinical analyses1,3,7
Companies exploring gene therapy options may cure SCD
There is a long list of companies (some of which are shown in Figure 3) exploring different technologies to treat SCD. Technologies include small molecules to biomolecules.8,9 An exhaustive list of potential therapeutics that are in clinical trials has been reviewed by Telen et. al.9 Gene therapy is also being explored to cure SCD. There are at least three different gene editing technologies currently being tested – Zinc Finger Nuclease, CRISPR and Peptide Nucleic Acids.8 These approaches are currently in different phases of clinical trial and will provide better outcomes to SCD patients, if successful.
Figure 3: Logos of companies involved in developing therapeutics for Sickle Cell Disease
1. Vichinsky, E. et. al., 2019, New England Journal of Medicine, 381, 6, 509-519
2. Centers for Disease Control and Prevention (accessed Jan 19th, 2020) https://www.cdc.gov/ncbddd/sicklecell/data.html
3. Niihara, Y. et. al., New England Journal of Medicine, 2018, 379, 3, 226-235
4. Metcalff, B. et. al., ACS Medicinal Chemistry Letters, 2017, 8,3,321-326
5. Ataga, K.I. et. al., New England Journal of Medicine, 2017, 376, 5, 429-439
6. Huo, J. Value in Health, 2018, 21, Suppl2, S108
8. Company websites (pipeline) (accessed Jan 19th, 2020)
9. Clinicaltrials.gov (accessed Jan 19th, 2020)
10. Telen, M.J. et. al. Nat. Rev. Drug Discov. 2019, 18, 139-158