Gene Therapies for Sickle Cell Disease

Abstract

Background: Sickle cell disease (SCD) is a prevalent autosomal recessive hemoglobinopathy affecting millions worldwide, particularly individuals of African ancestry. Sickle cell disease is a lifelong condition associated with a negative impact on quality of life and mortality, causing complications such as painful vaso-occlusive episodes, acute chest syndrome, stroke, long-term anemia, and end-organ damage. Currently, there are 4 U.S. Food and Drug Administration (FDA)-approved drugs, including hydroxyurea, l-glutamine, voxelotor, and crizanlizumab, which work to alleviate symptoms and prevent complications associated with SCD, albeit without addressing the underlying cause of SCD. Allogeneic hematopoietic stem cell transplant (HSCT) has shown promise as a curative approach to SCD but is limited by donor availability and associated complications. This paper aims to review the efficacy and safety of exagamglogene autotemcel and lovotibeglogene autotemcel for managing patients with SCD, including their place in therapy, cost, and accessibility in clinical care. Data Sources: The authors searched PubMed and Medline from 2017 to 2024, for primary literature on both exagamglogene autotemcel and lovotibeglogene autotemcel. Results: The authors identified relevant studies and summarized the data on the two gene therapies. Conclusion: Exagamglogene autotemcel and lovotibeglogene autotemcel are two management strategies that address the underlying cause of SCD and provide curative potential for patients with SCD.

Introduction

Sickle cell disease (SCD) is an autosomal recessive disorder affecting millions around the world and approximately 100,000 individuals in the United States.^1–3 Sickle cell anemia (SCA) is quite common and comprises about 70% of cases of patients with SCD who have African ancestry.^2–4 Sickle cell disease occurs due to replacing glutamic acid with valine at the sixth position of the β-globin chain, resulting in a tetramer hemoglobin S (HbS) in the red blood cells (RBCs). ⁵ Currently, 4 pathways characterize the clinical course of disease in SCD. ⁴ These pathways include vaso-occlusion, HbS polymerization, hemolysis-mediated endothelin dysfunction, and more recently, sterile inflammation. ⁴

Vaso-occlusion is characterized by ischemic events that lead to acute painful vaso-occlusive crises (VOC), causing patients with SCD to be often hospitalized. ⁴ Increased plasma viscosity results from long-term hemolysis and deformability of sickle cell RBCs due to dehydration and polymerization of hemoglobin. ⁶ This process impairs blood flow through postcapillary venules of high oxygen-demand tissues and capillaries. ⁶ Hemoglobin S polymerization occurs when the intraerythrocytic deoxygenation of high oxygen demand tissues contributes to the exposure of the hydrophobic component on individual deoxygenated HbS tetramers.^1,5,6 The different deoxygenated HbS tetramers bind tightly to form an HbS polymer.^1,5,6 The HbS polymers form elongated fibers after rapidly growing and thus increase cell rigidity and conform the erythrocyte membrane to cause sickling, cellular stress and energetic failure, dehydration, and premature hemolysis.^1,5,6

Less deformable HbS polymers are trapped in the microcirculation, leading to prolonged vaso-occlusion.^1,5,7,8 This process leads to extravascular and intravascular hemolysis causing long-term anemia and hemoglobin levels that range from 6 to 11 g/dL.^4,9-11 Patients with high rates of hemolysis are more likely to develop organ dysfunction and vascular injury that contributes to diastolic left heart disease, pulmonary hypertension, and renal dysfunction such as long-term kidney disease, proteinuria, and albuminuria.^9,12-15 Many studies have linked vaso-occlusion to the development of sterile inflammation.^7,8,16-19 Multiple episodes of reperfusion and vaso-occlusion lead to ischemia-reperfusion injury by causing transient hypoxia, activation of adaptive and innate immune responses, microvascular dysfunction, and cell death.^7,8,16-20

Management Strategies of SCD

In the United States, there are 4 Food and Drug Administration (FDA)-approved drugs to help prevent complications associated with SCD, with the first drug being hydroxyurea approved in 1998. ²¹ The next drugs were not FDA-approved until about almost 2 decades later: l-glutamine, in July 2017 and both voxelotor and crizanlizumab in November 2019.^21-24 These medications have been described extensively in the literature primarily for the management and prevention of VOC.^25-27 None of the current drug treatments address the underlying cause of the disease or fully remove the clinical manifestations seen in SCD. ²⁸ Therefore, newer management strategies now incorporate allogeneic hematopoietic stem cell transplant (HSCT) for SCD complications such as stroke. ²⁹ Allogeneic HSCT has been considered curative for patients with SCD; however, only about 20% of patients can find a related HLA-matched donor.^29,30 Patients undergoing allogeneic HSCT also contend with complications such as delayed immune reconstitution, graft-versus-host-disease (GVHD), infertility, or graft failure.^31,32 Consequently, another option is now available to patients with SCD in the form of an autologous HSCT using gene therapy.^28,32

Gene Therapy Overview

The 2 types of gene therapy include in vivo and ex vivo. In vivo, gene therapy requires direct delivery of a gene into a viral or nonviral vector and injection of the treatment into the patient. ³³ In contrast, ex vivo gene therapy is administered to cells extracted from the patient, which are genetically modified in culture, grown, expanded, and administered directly to the patient. ³³ The commonly used viral vectors include adenoviruses and adeno-associated viruses, while the less commonly used ones include lentiviruses, vaccinia viruses, poxviruses, and retroviruses. ³³ Nonviral vectors include lipid nanoparticles, polymers, inorganic materials such as carbon nanotubes, and peptide lipid vectors. ³⁴ Nonviral vectors, compared to viral vectors, tend to have less immunogenicity, handle a much higher payload, and have less cytotoxicity.^34,35 However, nonviral vectors have the disadvantage of having less transduction efficiency, physical and chemical instability, product storage, and inconsistency of the formulation preparation. ³³

In SCD, gene therapy corrects the pathophysiological abnormality by replacing an abnormal HbS with a normal functioning HbA or fetal hemoglobin (HbF). ³² Once a patient is considered a candidate for gene therapy, they receive RBC exchange transfusions, which suppress endogenous erythropoiesis for 60 days.^31,36,37 For SCD, generally, when hemoglobin increases beyond 11, it can cause hyperviscosity and sickling. The study by Frangoul and colleagues maintained the HbS to less than 30% and Hb around 10 to suppress hematopoiesis and improve the chances of better stem cell collection. ³⁷ This also decreases the risk of patients having a crisis before mobilization. Also, it is standard practice to keep Hb S <30% and Hb around 10 before starting transplant chemotherapy to minimize the risk of a VOC during the stress of chemotherapy conditioning. ³⁷ Afterward, the process is followed by mobilization and apheresis using plerixafor to collect CD34+ stem cells.^32,37 The cells are sent to a specialized manufacturing facility to be genetically modified through a viral or nonviral vector, and the process takes about 10 weeks to 6 months. ³⁶ Once the genetically modified cells are received, the patient receives myeloablative chemotherapy in the hospital. ³⁶ The modified cells are administered to the patient through a 1-time 10-minute infusion, with a recovery time of about 3 to 6 weeks. ³⁶ The modified cells undergo engraftment that leads to the production of new RBCs. ³⁶ The 2 novel ex-vivo nonviral and viral gene therapies, exagamglogene autotemcel and lovotibeglogene autotemcel, respectively, that were approved for SCD by the FDA were discussed. The article aimed to review the efficacy and safety, place in therapy, cost, and access to these gene therapies.

Literature Search

A literature search of PubMed and Medline was performed using the following search terms: “gene therapy,” “sickle cell disease,” and “treatment,” as well as a combination of these terms. English language randomized controlled trials in humans assessing the safety and efficacy of Exagamglogene autotemcel and lovotibeglogene autotemcel published between 2017 to 2024 were evaluated. Additional online searches were conducted via other search engines such as Lexicomp, Google Scholar, package inserts, and the Centers for Disease Control and Prevention (CDC) website for prescribing information, cost analysis, and updated guidelines. Bibliographies and abstracts of selected articles were reviewed manually for relevant publications focusing on the pathophysiology and overview of gene therapies in adults with SCD. Review articles (i.e., nonprimary literature sources) or articles in languages besides English were excluded. The results are summarized in Tables 1, 2, and 3.

Table 1.

Study Description and Participant Baseline Characteristics.

Citation	Study design	Interventions	Groups	Participants n	Median age (range)	Percent male	Percent patients with HbSS genotype	Annualized rate of severe VOCs a (events/year) median (min, max)	Annualized rate of hospitalization due to severe VOCs a (events/year) median (min, max)
Exagamglogene autotemcel [package insert] 38	Ongoing international, multicenter, single-arm, single-dose, phase 1/2/3, open-label study	Median exagamglogene autotemcel dose of 4.0 (range: 2.9, 14.4) × 106 cells/kg as an intravenous infusion	Full analysis set (FAS)	44	20 (12-34)	55	91	3.5 (2.0, 18.5)	2.5 (0.5, 9.5)
			Primary Efficacy Set b	31	21 (12-34)	55	97	3.5 (2.0, 18.5)	2.0 (0.5, 8.5)
Lovotibeglogene autotemcel [package insert] 39	Ongoing, multicenter, single-arm, open-label, phase 1/2 study	Median total dose of CD34+ cells was 6.9 × 106 cells per kilogram of body weight (range, 3.0 × 106 to 25.0 × 106), with a median LentiGlobin vector copy number of 3.7 copies (range, 2.3-5.7) per diploid genome	Full analysis set (FAS)	45	25 (12-43)	61	100	4 (0-27.5)
			Intention-to-treat, Group C (transplant population and transplant population with vaso-occlusive events.)	36	24 (12-38)			3.5 (0-13.5)

^aIn the 2 years before enrollment.

^bSubset of full analysis set (FAS) which included all patients who had been followed for at least 16 months after infusion.

Table 2.

Summary of Efficacy and Safety Outcomes.

	Exagamglogene autotemcel [package insert] 38	Lovotibeglogene autotemcel [package insert] 39
Primary endpoint	The proportion of subjects who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months Primary Efficacy Set: 93.5% (29/31), 98% CI (77.9%-100.0%)	Complete resolution of severe VOEs (sVOE-CR) between 6 and 18 months after infusion. Primary Efficacy Set: sVOE-CR: 94% (30/32), 95% CI (79%-99%)
Key secondary endpoint	The proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months Primary Efficacy Set: 100% (30/30), 98% CI (87.8 to 100.0%) Median duration of severe VOC free period in subjects who have achieved primary endpoint Primary Efficacy Set (n = 29): 22.2 (range: 14.8-45.5) months Mean proportion of total Hb comprised by HbF (%) of full analysis set 6 months (n = 38): 43.9% 24 months (n = 17): 42.1%	Complete resolution of any VOEs (VOE-CR) between 6 and 18 months after infusion. Primary Efficacy Set: VOE-CR: 88% (28/32), 95% CI (71%-97%) Globin response rates Primary Efficacy Set (n = 36): 86% (31/36)
Grade 3 or 4 nonlaboratory adverse reactions up to 24 months after infusion	(n = 44) Mucositis: 86% Febrile neutropenia: 48% Decreased appetite: 41% Musculoskeletal pain: 14% Abdominal pain: 11% Cholelithiasis: 11% Pruritus: 11%	(n = 45) Stomatitis: 71% Febrile neutropenia: 44% Sickle cell anemia with crises: 16% Decreased appetite: 11% Pharyngeal inflammation: 11%
Grade 3 or 4 laboratory abnormalities up to 24 months after infusion	(n=44) Neutropenia: 100% Thrombocytopenia: 100% Leukopenia: 98% Anemia: 84% Lymphopenia: 50% Decrease CD4 lymphocytes: 23% Prolonged activated partial thromboplastin time: 16% Hyperbilirubinemia: 14%	(n=45) Thrombocytopenia: 69% Neutropenia: 60% Anemia: 33% Leukopenia: 33% Aspartate aminotransferase increased: 18% Alanine aminotransferase increased: 13% Gamma-glutamyl transferase increased: 13%
Clinically relevant or Grade 1/2 adverse reactions	Veno-occlusive liver disease: 2% Infusion-related reactions: 14%

Table 3.

Advantages and Disadvantages of Gene Therapies in Sickle Cell Disease.

Gene Therapy	Advantages	Disadvantages
Exagamglogene autotemcel CRISPR–Cas9-based BCL11a-gene-editing therapy	1. FDA approved for patients 12 years and older 2. Reduced VOCs over a 12 month period 3. Reduced hospitalizations from VOCs 4. It increases the fetal hemoglobin levels in adult patients 5. Uses the CRISPR-Cas9 based technology leading to gene editing 6. Has an educational support and resource program for both patients and physicians called Vertex Connects	1. It requires a specialized center to administer the treatment 2. It is quite expensive and costs about $2.2 million for a single infusion 3. Patients have to be candidates for an autologous hematopoietic stem cell transplant to qualify to receive gene therapy 4. Follow-up required by the FDA for each patient is 15 years
Lovotibeglogene autotemcel Lentivirus-based gene therapy with HbAT87Q transgene	1. FDA approved for patients 12 years and older 2. Reduced VOCs over a 12 month period 3. Reduced hospitalizations from VOCs 4. It increases the hemoglobin A levels in adult patients 5. It undergoes gene addition by adding a functional copies of a modified form of the β-globin gene 6. Has a patient support program called my bluebird support to help them navigate the treatment process	1. It requires a specialized center to administer the treatment 2. It is quite expensive and costs about $3.1 million for a single infusion 3. Patients have to be candidates for an autologous hematopoietic stem cell transplant to qualify to receive gene therapy. 4. Some patients have developed leukemias as a result of receiving Lovotibeglogene autotemcel 5. Follow-up required by the FDA for each patient is 15 years

Exagamglogene Autotemcel

Mechanism of Action

Exagamglogene autotemcel is FDA-approved for the treatment of SCD in patients 12 years of age or older with recurrent VOC. ³⁸ It is an autologous ex vivo, nonviral genome-edited hematopoietic stem cell-based gene therapy using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease system. ³⁸ This system utilizes a bacterial immune system to cleave bacteriophage or plasmid DNA, allowing targeted insertions or deletions at specific genomic DNA sites.^40,41 The CD34+ hematopoietic stem and progenitor cells obtained from patients undergo electroporation utilizing CRISPR-Cas9 gene-editing techniques targeting the BCL11A erythroid-specific enhancer region. ²⁸ BCL11A is a transcription factor suppressing γ-globin expression and fetal hemoglobin in erythroid cells.^42,43 The γ-globin is a protein chain that makes up HbF in RBCs.^44,45 The patient then receives autologous CD34+ cells edited with CRISPR-Cas9. ²⁸ After administration of exagamglogene autotemcel, the edited CD34+ cells engraft in the bone marrow and differentiate to erythroid lineage cells with reduced BCL11A expression, resulting in an increase in γ-globin expression and HbF protein production in erythroid cells. ³⁸ Increased HbF expression addresses the underlying pathophysiology of the disease by preventing RBCs from sickling in the first place by reducing intracellular HbS concentration. ³⁸ By preventing the production of sickled RBCs, exagamglogene autotemcel was able to eliminate VOCs.^38,46,47

Methods

The efficacy of exagamglogene autotemcel was evaluated in an ongoing international, multicenter, single-arm, single-dose, phase 1/2/3, open-label trial with patients 12 to 35 years of age with SCD.^37,38 Patients had to experience 2 or more severe VOCs per year in the 2 years before screening. Severe VOC was defined as the occurrence of any of the following: acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous nonsteroidal anti-inflammatory drugs) or RBC transfusions, acute chest syndrome, priapism lasting >2 hours and requiring a visit to a medical facility or splenic sequestration.^37,38 Patients had to be eligible for autologous HSCT. In addition, patients aged 12 to 16 years were required to have normal transcranial Doppler.^37,38

Patients were required to discontinue the use of hydroxyurea, voxelotor, and crizanlizumab at least 8 weeks before the start of mobilization and conditioning.^37,38 Patients were required to discontinue the use of iron chelators at least 7 days before the start of myeloablative conditioning with busulfan and avoid the use of nonmyelosuppressive and myelosuppressive iron chelators for at least 3 months, and 6 months respectively postinfusion.^37,38 Female participants of childbearing age required a negative pregnancy test before the start of each mobilization cycle and reconfirmed before myeloablative conditioning. Women of childbearing potential and men capable of fathering a child used effective methods of contraception from the start of mobilization through at least 6 months after administration of exagamglogene autotemcel.^37,38

Forty-four patients received treatment with exagamglogene autotemcel. Twelve out of the 44 patients were adolescents between the age of 12 to 18 years.^37,38 Patients were administered exagamglogene autotemcel at a median dose of 4.0 (range: 2.9, 14.4) × 106 cells/kg as an intravenous infusion, with a median duration of follow-up of 19.3 (range: 0.8-48.1) months.^37,38 All patients underwent mobilization and apheresis, with RBC exchange or simple transfusions, for at least 8 weeks before mobilization and continued receiving transfusions or RBC exchanges until the start of myeloablative conditioning.^37,38 Hemoglobin S levels were maintained at less than 30% of total Hb while keeping total Hb concentration ≤11 g/dL. To mobilize stem cells for apheresis, all patients were administered plerixafor at a dose of 0.24 mg/kg via subcutaneous injection 2 to 3 hours before apheresis.^37,38 The mean number of mobilization and apheresis cycles required for the manufacture of exagamglogene autotemcel and for the backup collection of rescue CD34+ cells were 2.3 and 2, respectively.^37,38

All patients received full myeloablative conditioning with busulfan before treatment with exagamglogene autotemcel.^37,38 Busulfan was administered at a starting dose of 3.2 mg/kg/day once daily or 0.8 mg/kg every 6 hours intravenously via central venous catheter for 4 consecutive days.^37,38 Busulfan plasma levels were measured by serial blood sampling, and the dose was adjusted to maintain exposure in the target cumulative range (once daily dose: 82 mg*h/L, range: 74-90 mg*h/L; every 6 hours dose: 74 mg*h/L, range: 59-89 mg*h/L).^37,38 Owing to the risk of seizures and hepatic sinusoidal obstruction syndrome with busulfan use, all patients received antiseizure prophylaxis before initiating busulfan conditioning.^37,38 Of note, phenytoin was not used for antiseizure prophylaxis due to the cytochrome P-450 (CYP450) induction, which increased busulfan clearance.^37,38 Hepatic veno-occlusive disease and hepatic sinusoidal obstruction syndrome prophylaxis were administered based on regional and institutional guidelines.^37,38

Efficacy

All patients achieved neutrophil engraftment by day 42, and no patients received backup CD34⁺ cells.^37,38 The primary efficacy endpoint was the proportion of patients who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion.^37,38

Efficacy was evaluated based on an interim analysis of the primary efficacy set of 31 patients, which was a subset of the full analysis set. The primary efficacy set included patients who had been followed for at least 16 months after exagamglogene autotemcel infusion.^37,38 Patients with less than 16 months of follow-up due to death or discontinuation due to adverse events related to the treatment or who continuously received RBC transfusions for more than 10 months after treatment were also included in the primary efficacy set.^37,38 An additional patient who had less than 16 months of follow-up but was otherwise determined to be a nonresponder for the primary efficacy endpoint was also included.^37,38

At baseline, patients in the primary efficacy set had a median of 3.5 (range: 2.0-18.5) severe VOCs/year in the 2 years before enrollment and a median of 2.0 (range: 0.5-8.5) annualized rate of hospitalization due to severe VOCs in the 2 years before enrollment.^37,38 Most patients were African American (87%, 27/31) and had a genotype of HbSS (97%, 30/31).^37,38 Around 93% (29/31) of patients met the primary efficacy endpoint of the proportion of patients who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel infusion (98% CI, 77.9%-100%). Seven of the 31 patients in the primary efficacy set were adolescents.^37,38 The evaluation started 60 days after the last RBC transfusion for posttransplant support or SCD management.^37,38 The median time to last RBC transfusion after exagamglogene autotemcel infusion for patients in the primary efficacy set was 19 (range: 11-52) days.^37,38 The median time to platelet engraftment was 45 (range: 23-81) days in pediatric/adolescent patients and 32 (range: 23-126) days in adult patients.^37,38 The median time to neutrophil engraftment was 28 (range: 24-40) days in pediatric/adolescent patients and 26 (range: 15-38) days in adult patients. Of note, one patient who met the primary endpoint experienced a severe VOC at 22.8 months, requiring a 5-day hospitalization and was found to be positive for parvovirus B19 infection.^37,38

Almost 100% of the patients (30/30) met the key secondary endpoint defined as the proportion of patients free from inpatient hospitalization for severe VOCs sustained for at least 12 consecutive months after exagamglogene autotemcel infusion (98% CI, 87.8%-100%). One patient was not evaluable and thus excluded from the key secondary endpoint analysis.^37,38 Exagamglogene autotemcel increased mean HbF levels to 43.9% at month 6, and sustained levels to 42.1% at 2 years in the full analysis set of 44 patients.^37,38

Safety

The safety of exagamglogene autotemcel was evaluated in 44 adolescent and adult patients with SCD who received a single dose of exagamglogene autotemcel after undergoing myeloablative conditioning with busulfan, evaluated up to 2 years after exagamglogene autotemcel infusion.^37,38 The most common grade 3 or 4 nonlaboratory adverse reactions were mucositis (86%, 38/44), followed by febrile neutropenia (48%, 21/44), decreased appetite (41%, 18/44), musculoskeletal pain (14%, 6/44), abdominal pain (11%, 5/44), cholelithiasis (11%, 5/44), and pruritus (11%, 5/44).^37,38 Clinically important grade 1 or grade 2 veno-occlusive liver disease occurred in (2%, 1/44) of patients. Infusion-related reactions occurred in 14% (6/44) of patients.^37,38 The most common grade 3 or 4 laboratory abnormalities were neutropenia and thrombocytopenia, occurring in all patients, followed by leukopenia (98%), anemia (84%), lymphopenia (50%), decreased CD4 lymphocytes (23%), prolonged activated partial thromboplastin time (16%), and hyperbilirubinemia (14%).^37,38 There were no reported GVHD, graft failure, or graft rejection cases. One patient died due to a COVID-19 infection, and subsequent respiratory failure was found to be unrelated to exagamglogene autotemcel infusion.^37,38

Lovotibeglogene Autotemcel

Mechanism of Action

Lovotibeglogene autotemcel (formerly lovo-cel or LentiGlobin) is FDA approved for the treatment of SCD in patients ages 12 years or older with a history of VOC. ³⁹ It is an ex vivo lentiviral gene therapy that consists of autologous CD34+ hematopoietic stem and progenitor cells harvested from patients’ bone marrow or peripheral blood.^39,48 The extracted CD34+ HSCs are transduced with the BB305 lentiviral vector (LVV) encoding a functional human β^A-T87Q-globin gene (with an amino acid substitution of threonine [T] replaced with glutamine [Q] at position 87, T87Q).^39,48 The BB305 LVV integrates the functional β^A-T87Q-globin gene into the patient’s genome, producing antisickling hemoglobin.^39,48 The modified hematopoietic stem cells are then infused back into the patient via stem cell transplant, where they engraft and differentiate into mature blood cells that can produce healthy hemoglobin A (HbA), in place of abnormal HbS.^39,48 The healthy and functional HbA has a higher affinity for oxygen than HbS. It does not cause the characteristic sickling, preventing the abnormal shape of RBCs and reducing subsequent VOCs and other SCD-related complications. ⁴⁹ The precise mechanism for the mitigated reduction in VOCs is complex and may involve multiple factors that can influence the disease process. ⁴⁹ The use of lovotibeglogene autotemcel for the treatment of SCD is manufactured specifically for each of its recipients and is intended for 1-time intravenous administration. ³⁹

Methods

The efficacy of lovotibeglogene autotemcel was evaluated in a multicenter, single-arm, open-label, phase 1/2 study in patients between 12 and 50 years of age with SCD. ⁵⁰ In this phase 1/2 study, patients were evaluated for 24 months, followed by a 13-year follow-up study.^50,51 This study established 3 experimental groups, specifically focusing on Group C (n = 36) for this report as it related to efficacy outcomes. (Supplemental Appendix A) Group C was specifically created to evaluate the efficacy of lovotibeglogene autotemcel treatment that involved cells collected through plerixafor mobilization and apheresis, and then transduced with the BB305 LVV. Eligible patients had to experience a minimum of 4 severe VOCs in the past 24 months before enrollment.^39,48 Other inclusion criteria included: a diagnosis of SCD with an HbSS, HbSβ+-thal, and HbSβ0-thal genotype, a clinically stable Karnofsky performance status of at least 60 (for patients ≥16 years of age) or a Lansky performance status of at least 60 (for those <16 years of age), past treatment failure of standard of care with hydroxyurea, a 2-year history of active treatment of SCD before enrollment, and no opportunity for matched HLA-identical hematopoietic-cell donation. ⁴⁸

All patients underwent mobilization and apheresis, with either a simple or exchange RBC transfusion regimen for at least 60 days (8 weeks) before HSPC collection. ⁵² Patients continued receiving transfusions or RBC exchanges until the start of myeloablative conditioning. ⁵² Hemoglobin S levels were maintained at less than 30%, with a Hb target of 10 g/dL (not exceeding 12 g/dL). ⁵² To mobilize stem cells for apheresis, all patients were administered plerixafor at a dose of 0.24 mg/kg via subcutaneous injection, followed by apheresis within 4 to 6 hours of plerixafor. ⁵² The target number of cells to be collected by plerixafor mobilization and apheresis was ≥10 × 10⁶ CD34+ cells/kg, with 1.5 × 10⁶ CD34+ cells/kg reserved for rescue. ⁵² Each mobilization cycle permitted up to 2 serial apheresis procedures after daily plerixafor. If too few cells were collected during the first mobilization cycle, another cycle, staggered by at least 2 weeks, was allowed. ⁵²

Patients receiving lovotibeglogene autotemcel were required to discontinue the use of hydroxyurea, voxelotor, l-glutamine, crizanlizumab, and erythropoietin at least 2 months before the start of mobilization. ³⁹ Iron chelation therapy should be discontinued 7 days before mobilization and conditioning. Prophylactic HIV antiretroviral therapy should also be discontinued at least 4 weeks before mobilization and until all cycles of apheresis are complete. ³⁹ Patients should be screened for HIV-1/2 before use, as lovotibeglogene autotemcel has not been studied in patients living with HIV. ³⁹ Female participants of childbearing age were required to have a negative pregnancy test before the start of each mobilization cycle and reconfirmed before conditioning and before administration of lovotibeglogene autotemcel. ³⁹ Women of childbearing potential and men capable of fathering a child used effective methods of contraception from the start of mobilization through at least 6 months after administration of lovotibeglogene autotemcel. ³⁹

Myeloablative conditioning with busulfan should not begin until the complete set of infusion bag(s) constituting the dose of lovotibeglogene autotemcel has been both received and stored at the treatment center and the availability of the backup collection is confirmed. ³⁹ Busulfan was administered at a starting dose of 3.2 mg/kg/day once daily or 0.8 mg/kg every 6 hours intravenously via central venous catheter for 4 consecutive days and must be administered before lovotibeglogene autotemcel. ³⁹ Pharmacokinetic monitoring after the first dose and dose should be adjusted to achieve the target AUC (target AUC is 5000 [range: 4400-5400] μM*min for a once-daily dosing regimen and 1250 [range: 1100-1350] μM*min for a q6h dosing regimen). Owing to the risk of seizures and hepatic sinusoidal obstruction syndrome with busulfan use, all patients also received antiseizure prophylaxis at least 12 hours before initiating busulfan conditioning. Phenytoin was avoided because of CYP450 induction, leading to an increase in busulfan clearance.

Efficacy

The efficacy outcomes were complete resolution of all VOCs and severe VOCs between 6 months and 18 months after infusion of lovotibeglogene autotemcel. ⁴⁸ A vaso-occlusive event was defined as an episode of acute pain with no medically determined cause other than a vaso-occlusion. It included acute episodes of pain, acute chest syndrome, acute hepatic sequestration, acute splenic sequestration, and acute priapism. ⁴⁸ A severe vaso-occlusive event was defined as an event that resulted in a visit to a hospital or emergency department that exceeded 24 hours, had 2 visits that required intravenous treatment to a day unit or emergency department during a 72-hour period, or a priapism episode that lasted more than 2 hours and led to a medical-facility visit. ⁴⁸ The median of severe VOCs was 3.5 events per year (range: 2.0-13.5) 24 months before enrollment.^39,48

During the treatment process, patients received a median of 2 mobilization cycles (range: 1-4). Patients were administered lovotibeglogene autotemcel as an intravenous infusion at a median (min, max) dose of 6.4 (3, 14) CD34+ cells/kg. ³⁹ A median of 80% of CD34+ cells (range: 63-93) were positive for BB305 LVV. ³⁹ The median BB305 LVV copy number in peripheral blood was at least 1.1 copies/diploid genome. ³⁹ All 36 patients infused in Group C were evaluated for globin response, with 86% (31/36) achieving globin response and all patients maintaining globin response once it was achieved. ³⁹ Patients had a month 6 median (min, max) HbA^T87Q of 5.2 (2.6, 8.8) g/dL (N = 33). Hemoglobin A^T87Q remained durable with a median (min, max) of 5.5 (2.4, 9.4) g/dL at month 24 (N = 34). Hemoglobin A^T87Q comprised a median (min, max) 45.7% (26.9, 63.2) (N = 34) of total nontransfused hemoglobin at month 24. ³⁹ The median total hemoglobin value increased from a baseline of 8.5 to 11 g/dL at 6 months and was sustained through 36 months, with HbA^T87Q contributing to at least 40% of total hemoglobin and was distributed across a mean (±SD) of 85% ± 8% of RBCs. ³⁹ Overall, 88% (28/32, 95% CI: 71-97) of patients in the transplant group were found to have a complete resolution in VOCs, and 94% had a complete resolution in severe VOCs (30/32, 95% CI: 79-99). ³⁹

In the study, the median duration of follow-up was 38 months post lovotibeglogene autotemcel infusion. From the primary evaluation period to the last follow-up, 4 of 32 patients who achieved a complete resolution of VOCs had experienced VOEs while maintaining globulin response. ³⁹ From the primary evaluation period up to 24 months, 17 of 35 (49%) patients were prescribed opioids for sickle cell and nonsickle cell-related pain. ³⁹

Safety

The safety of lovotibeglogene autotemcel reported here is based on patients in Groups A, B, and C (n = 45) in one open-label, single-arm clinical trial.^39,48 Mobilization and apheresis triggered severe adverse events (SAEs) of sickle cell crisis in (14%, 6/44) patients who initiated mobilization in the intent-to-treat population. ⁴⁸ All patients who initiated conditioning (100%, 45/45) experienced at least one adverse event attributed to conditioning and were related to the known effects of alkylating agents.^39,48 Seventy-three percent of patients on lovotibeglogene autotemcel experienced at least a grade 3 or higher adverse event. Most Grade 3 or higher laboratory abnormalities include increased aspartate aminotransferase (18%), increased alanine aminotransferase (13%), increased gamma-glutamyl transferase (13%), thrombocytopenia (69%), neutropenia (60%), anemia and leukopenia (33%), respectively. ³⁹ Patients with grade 3 or higher nonlaboratory adverse effects included stomatitis (71%), febrile neutropenia (44%), sickle cell anemia with crises (16%), decreased appetite, and pharyngeal inflammation (11%), respectively. Overall, 3 adverse events were attributed to lovotibeglogene autotemcel infusion, including leukopenia, hypotension, and febrile neutropenia. ⁴⁸ One death occurred 20 months after infusion in a patient with cardiopulmonary disease related to SCD at baseline. ⁴⁸ Hematologic malignancy (blood cancer) occurred in patients treated with lovotibeglogene autotemcel with a black box warning included on the label regarding this risk. ³⁹

Discussion

Gene therapies have been recently approved in the past years for patients with conditions such as beta-thalassemia, hemophilia, spinal muscular atrophy, inherited retinal disorder, cerebral adrenoleukodystrophy, and Duchenne muscular dystrophy ⁵³ Gene therapy is potentially a viable alternative treatment that could be considered curative for some patients. Nevertheless, there are many things to consider when selecting a patient for gene therapy. Both exagamglogene autotemcel and lovotibeglogene autotemcel were approved in December 2023. However, very little is known about their long-term safety and efficacy. ⁵⁴ The FDA provided guidance in 2020 on collecting data on delayed adverse events in long-term follow-up studies of gene therapies.^54,55 These guidelines stipulated that the studies using adeno-associated viral vectors had a 5-year minimum follow-up period.^54,55 Studies incorporating vectors and genome editing procedures had a minimum 15-year follow-up period.^54,55

There are criteria that patients with SCD have to meet to be considered for gene therapy. ⁵⁶ First and foremost, they have to be at least 12 years of age and older and then have SCD genotype classified as HbSS, HbSβ+-thal and HbSβ0-thal for lovotibeglogene autotemcel, and HbSS and HbSβ0-thal for exagamglogene autotemcel. ⁵⁶ Third, they had to be diagnosed with severe SCD, which was defined in the clinical trials as either having 4 VOCs over a 2-year period or having 2 VOCs per year over 2 years. ⁵⁶ Gene therapies are usually offered to patients with SCD who also meet the inclusion criteria for a curative allogeneic bone marrow transplantation. ⁵⁷ Therefore, these patients should have adequate organ function before receiving the high-dose chemotherapy in the conditioning regimen. ⁵⁷ Furthermore, they should be counseled on the short- and long-term consequences of chemotherapy, including the ability to cause infertility and act as a carcinogen. ⁵⁷ The feasibility of receiving gene therapy has been limited to specialized centers in the developed world which have expertise in transplant in SCD. ⁵⁷

Many of the patients living with SCD are in low-resource settings and have zero or limited access to comprehensive care of SCD management. ⁵⁸ A study by Dua and colleagues identified factors such as inadequate health care facility infrastructure, limited laboratory monitoring, inadequately trained personnel, and unavailability of medicines that contributed to barriers to access to sickle cell-based care. ⁵⁸ A scoping review conducted by Drown and colleagues evaluated models of care for SCD in low-income countries (LICs) and low-middle-income countries (LMICs) and found that these models that incorporated integration of care were found in 2 countries, namely Angola and Kenya. ⁵⁹ These integrated models of care were also found to be concentrated in urban specialized SCD centers, with one rural model found in India. ⁵⁹ Therefore, the ex vivo gene modification model in both LIC and LMIC would not be feasible, given the lack of infrastructure to support this treatment option. However, in 2019, the National Institutes for Health (NIH) collaborated with the Bill and Melida Gates foundation to invest $200 million to develop affordable global gene-based cures for SCD and HIV in low-resource countries. ⁶⁰

Lifetime medical costs for patients with SCD aged between 0 and 64 years who are on commercial insurance are estimated to be about $1.6 million for females and $1.7 million for males. ⁶¹ This is already a substantial economic burden on patients living with SCD, and it is expected to increase over time. ⁶¹ A large percentage of this cost is due to the high rate of inpatient admissions of patients presenting with VOCs. ⁶¹ Therefore, the recent approval of the 2 new gene therapies can potentially decrease the rate of hospitalizations from VOCs. ⁵⁶ Patients with severe SCD who are considered for exagamglogene autotemcel and lovotibeglogene autotemcel have an average cost of $2.2 million and $3.1 million, respectively, for a full course of treatment. This high cost makes it inaccessible to many patients, and many payers might be reluctant to foot such a high bill upfront. ⁶¹ A study by Philips and colleagues evaluated the perspectives of patients with SCD on barriers to care. ⁶² They found that these patients had multiple barriers, which included family/interpersonal, individual, and socio-environmental/organizational care. ⁶² The results showed that inadequate medicine coverage and high co-pays were the most commonly reported insurance-related barriers to care. ⁶²

Exagamglogene autotemcel and lovotibeglogene autotemcel are expected to be administered in an inpatient setting and, because they are directly reimbursed, would be considered covered outpatient drugs. ⁶³ Therefore, to help alleviate the burden of high costs, the Centers for Medicare and Medicaid Services (CMS) has proposed a payment model that is based on patient outcomes starting from January 2025. ⁶³ This program will reduce patients’ costs since about 50% to 60% of patients with SCD are on Medicaid. ⁶³ The Cell and Gene therapy (CGT) access model voluntary program allows states Medicaid agencies and manufacturers to delegate authority to CMS to establish multistate frameworks to pay for gene therapy. ⁶³ The CGT access model aims to provide Medicaid beneficiaries with improved health outcomes, access to innovative therapies, and reduced health care costs to state programs. ⁶³ The model will be expanded to include fertility preservation after myeloablative chemotherapy, ancillary support for case management, travel expenses, and behavioral services. ⁶³

A recently released report by the Institute for Clinical and Economic Review (ICER) conducted a comparative clinical effectiveness and value analysis of exagamglogene autotemcel and lovotibeglogene autotemcel. ⁵⁶ They surmised that the effectiveness of both therapies was similar due to a small number of participants using a model that compared them to standard care. ⁵⁶ Standard care was defined as having an individual on hydroxyurea, supportive care for VOCs or other acute and long-term complications, and as-needed blood transfusions. ⁵⁶ The panel found that when patients with severe SCD were compared to standard care and lovotibeglogene autotemcel, there was an incremental net benefit with a rating of B+. ⁵⁶ However, the patients with severe SCD were compared to standard care and exagamglogene autotemcel, and there was a comparable net benefit with a rating of C++. ⁵⁶ A rating of B+ was defined as “incremental or better,” while a rating of C++ was defined as “comparable or better” than standard treatment. The exagamglogene autotemcel received a rating of C++ because it has similar concerns but more uncertainty due to CRISPR therapy being newer than lentiviral therapy. ⁵⁶ Nevertheless, when comparing the 2 gene therapies, the evidence was rated as insufficient because they have different mechanisms of action. Future research will probably provide information on the safety and effectiveness. ⁵⁶ The panel also found that the Health Benefit Price Benchmark (HBPB) for both therapies was estimated to be between $1 350 000 to $2 050 000. ⁵⁶

Conclusion

The recent emergence of cell-based gene therapy presents a promising avenue for addressing the underlying pathophysiological abnormalities of SCD. By targeting key factors such as increased fetal hemoglobin (HbF) production and genetic modification to produce hemoglobin A (HbA)—ultimately leading to the suppression of HbS, gene therapy offers a potentially curative approach to SCD. Yet, despite the approval of novel gene therapies such as exagamglogene autotemcel and lovotibeglogene autotemcel, significant challenges remain, including accessibility, affordability, and long-term safety and efficacy. Future research and clinical experience will be crucial in elucidating the true impact of gene therapy on improving outcomes for individuals living with SCD and optimizing its integration into comprehensive care management strategies.