Two groundbreaking cell-based gene therapies, exagamglogene autotemcel and lovotibeglogene autotemcel, were recently approved by the FDA for the treatment of sickle cell disease.
Sickle cell disease (SCD) is a genetic disorder affecting millions globally, predominantly in regions with a historical prevalence of malaria. The disease, characterized by the presence of abnormal hemoglobin, leads to various complications impacting multiple organ systems. This article reviews the epidemiology, pathophysiology, complications, and conventional management strategies for SCD. Additionally, it highlights the recent FDA approvals of 2 groundbreaking cell-based gene therapies, exagamglogene autotemcel (Casgevy; Vertex Pharmaceuticals) and lovotibeglogene autotemcel (Lyfgenia; Bluebird Bio, Inc), which represent a significant leap forward in SCD treatment.
Sickle cell disease (SCD) poses a significant health burden, particularly among populations with historical ties to malaria-endemic regions. The genetic mutation causing SCD results in abnormal hemoglobin, leading to a cascade of complications that affects various organ systems.
SCD is caused by a single amino acid mutation (valine instead of glutamate at the 6th position) in the beta chain of the hemoglobin gene. Due to its recessive inheritance pattern, individuals who inherit this mutated gene from both parents develop sickle cell disease, which is associated with a shorter life expectancy due to its complications. Conversely, individuals who are carriers of the sickle cell trait (with 1 sickle gene and 1 normal hemoglobin gene) have some protective advantage against malaria and do not experience the severe symptoms of SCD. As a result, the frequency of sickle cell carriers is high in malaria-endemic areas.1
SCD affects millions of people worldwide with a tendency to affect regions with a history of malaria such as sub-Saharan Africa, South Asia, the Middle East, and the Mediterranean.2 SCD is also the most common inherited blood disorder in the United States affecting between 70,000 to 100,000 people, a majority of whom are African American or Hispanic.3 A study conducted by the American Society of Hematology (ASH) reported that in 2020, there were an estimated 120,000 cases of SCD identified, with US-born patients accounting for approximately 87% of this number, and immigrants accounting for the remaining percent, with the highest number of cases occurring in Florida. The authors of the ASH study suggest that the number of cases from national studies may be underestimated due to the use of new-born screening methods, which do not account for cases among immigrants.4 A study done by the Institute for Health Metrics and Evaluation (IHME) also mentioned that from 2000 to 2021 there was a global increase of SCD cases by roughly 14%.5
Due to complications that arise from SCD, such as anemia and vascular occlusions, this disease often results in a shortened life expectancy of potentially more than 20 years, and up to 30 years decreased quality-adjusted life expectancy. IHME estimates that in 2021, the total global mortality due to SCD was about 376,000, which is approximately 11 times higher than that of other cause-specific deaths across all ages. Additionally, in children younger than 5 years old, SCD ranked 12th in mortality across all causes.5
The single amino acid mutation in the beta chain of the hemoglobin gene triggers polymerization of deoxygenated hemoglobin, altering erythrocyte shape and function. This polymerization which alters erythrocytes into the sickled shape of the disease namesake is the trigger of the high risk complications which include vaso-occlusive crises, tissue damage, and inflammation. Due to the mechanism of the disease, treatment therapies largely focus on inhibiting polymerization as well as managing the resulting cells. The polymerization process can be inhibited by increasing fetal hemoglobin (HbF), decreasing sickle hemoglobin (HbS), or increasing hemoglobin-oxygen affinity.6
Following polymerization, sickled cells can cause cuts and damage to the blood vessels leading to inflammation. Image Credit: © Studios - stock.adobe.com
SCD can manifest as vaso-occlusive crises, acute chest syndrome, infections, pulmonary hypertension, cerebrovascular accidents, and many other complications. Following polymerization, sickled cells can cause cuts and damage to the blood vessels leading to inflammation. Sickled cells are broken down more rapidly than normal cells leading to anemia and reduced oxygen flow manifesting as subsequent dizziness and fatigue. In addition, sickled cells lead to frequent blockages of blood flow (vaso-occlusive crises) which can cause stroke, ischemia, infarction, avascular necrosis, and renal insufficiency in patients starting as early as 5 months old.3 As a result, life expectancy for individuals with SCD is calculated to be 53 years compared to the average life expectancies of 74 years for men and 79 years for women.Management strategies encompass health maintenance and addressing complications promptly.7
Current SCD management involves health maintenance through risk factor identification and early complication detection. Previously approved drug therapies indicated for SCD management include hydroxyurea, voxelotor (Oxbryta; Global Blood Therapeutics), and crizanlizumab (Adakveo; Novartis Pharmaceuticals Corporation). Hydroxyurea was FDA approved in 2017 for patients aged 2 and older to prevent recurrent moderate to severe sickle cell crises; it works to avert the polymerization of HbS by increasing levels of HbF. Initial recommended dosing of hydroxyurea is 20 mg/kg administered once daily.8
The HOPE trial evaluated voxelotor, an HbS polymerization inhibitor, in adults and children 12 years and older; the trial showed significant improvements in hemoglobin levels and reduced markers of hemolysis. Voxelotor (Oxbryta; Global Blood Therapeutics) is a once-daily oral drug approved in 2019 for patients 12 and older. As of 2022, voxelotor was also approved for use in patients aged 4 to 11 years. Recommended dosing for patients 12 and older is 1500 mg orally while dosing for ages 4 to 11 years is weight based.9 Crizanlizumab is a monoclonal antibody that inhibits binding to p-selectin, which is a contributor to vaso-occlusive events and pain events in patients with SCD. High-dose crizanlizumab (5 mg/kg) demonstrated a significant decrease in these events in comparison to placebo in the SUSTAIN trial.10 The FDA approved crizanlizumab in 2019 for adults and children 16 years and older to reduce the frequency of vaso-occlusive events associated with SCD.
Taylor Eleola and Krystle Imamura are fourth-year pharmacy students attending the University of Hawaii at Hilo Daniel K. Inouye College of Pharmacy.
Olatunji Gbadebo, PharmD, is a class of 2024 alumni of the University of Hawaii at Hilo Daniel K. Inouye College of Pharmacy.
Funding source: No funding
Recent FDA approvals as of December 2023, exagamglogene autotemcel (Casgevy; Vertex Pharmaceuticals) and lovotibeglogene autotemcel (Lyfgenia; Bluebird Bio, Inc) represent the first cell-based gene therapies for SCD patients aged 12 and older.
Exagamglogene Autotemcel
Exagamglogene autotemcel is a 1-time therapy used to treat SCD with frequent vaso-occlusive events. It had an estimated cost of $2.2 million.12 Exagamglogene autotemcel was developed through the CLIMB SCD-121 trial and utilizes ex vivo CRISPR-Cas9 gene editing to reactivate HbF via autologous CD34+ hematopoietic stem and progenitor cells by targeting the BCL11A gene. Reducing BCL11A expression would result in the body starting to produce an increased level of HbF.13 In clinical trials, the therapy demonstrated impressive efficacy, with 97% of patients free from severe vaso-occlusive crises for at least 12 months.14
A dose of at least 3×106 CD34+ cells/kg given intravenously is recommended for SCD therapy. For at least 8 weeks prior to starting therapy with exagamglogene autotemcel, patients should be maintained at a goal of HbS less than 30%, total hemoglobin must be maintained at 11 g/dL or less, and all disease-modifying medications such as hydroxyurea or combination therapy with voxelotor and crizanlizumab should be stopped. Patients should also discontinue any granulocyte colony-stimulating factor and iron chelators at least 7 days prior to initiation. Due to its respective mechanism as a gene therapy, no CYP 450 interactions or drug transporter interactions have been found at this time.15 Possible adverse effects (AEs) include low platelets (eg, bruising, prolonged bruising, or bleeding without injury) and low white blood cell count (eg, fever, chills, infection).
Delayed platelet engraftment presents an increased risk until engraftment is achieved. Potential AEs include neutrophil engraftment failure as well as off-target genome editing risk; however, it should be noted that neither events were experienced by subjects within the trial.13
Lovotibeglogene Autotemcel
Lovotibeglogene autotemcel is a 1-time gene therapy for patients 12 years and older with a history of vaso-occlusive events that works by adding functional copies of the HBB gene to blood stem cells to allow the body to produce functional adult hemoglobin.16 The estimated price of lovotibeglogene autotemcel is higher than exagamglogene autotemcel at $3.1 million.12 Lovotibeglogene autotemcel utilizes a lentivirus to deliver a functional hemoglobin-producing gene within the patient genome. Lovotibeglogene autotemcel is supported by the HGB-206 study which showcased remarkable outcomes. A substantial percentage of treated patients achieved complete resolution of vaso-occlusive events, indicating a significant breakthrough in SCD treatment.17
The recommended dose for lovotibeglogene autotemcel is the same as for exagamglogene autotemcel: a minimum of 3×106 CD34+ cells/kg given intravenously. Disease-modifying medications should also be discontinued for 2 months prior to initiating lovotibeglogene autotemcel, including L-glutamine and erythropoietin in addition to hydroxyurea and combination treatment voxelotor and crizanlizumab. Iron chelation should be discontinued 7 days prior to therapy, and antiretrovirals should be discontinued 1 month prior, though it should be noted that certain antiretrovirals may require longer washout periods. The most common AEs of lovotibeglogene autotemcel include low platelets, white cells, and blood cells, febrile neutropenia, and stomatitis. Metabolism and drug metabolism effects are unknown at this time. Lovotibeglogene autotemcel also has a black box warning for occurrence of blood cancer during treatment, which warrants complete blood counts every 6 months.18
The recent FDA approvals of exagamglogene autotemcel and lovotibeglogene autotemcel mark a transformative era in SCD therapy and offers hope for improved outcomes and a potentially curative approach for patients with severe SCD. These medications present a large leap in SCD treatment due to 1-time dosing as well as the introduction of gene therapy. The respective costs of these gene therapies act as the main barrier preventing widespread implementation into practice. Further research and long-term monitoring will be crucial to assess the sustained efficacy and safety of these novel treatments.
