What information is available on novel gene therapies for treatment of sickle cell disease?

Introduction
Approximately 100,000 people in the United States are affected by sickle cell disease (SCD).¹ The disease occurs most commonly among those who are descendants from sub-Saharan Africa, Spanish-speaking areas within the Western Hemisphere, Saudi Arabia, India, and various Mediterranean countries. The presentation of SCD varies greatly depending on genotype, with patients who are homozygous for the sickle cell hemoglobin (HbS) mutation experiencing more severe, sometimes life-threatening disease and those who are heterozygous for the mutation often experiencing less severe disease that presents later in life.² Sickled red blood cells cause a variety of complications, including chronic hemolytic anemia and vasoocclusion, an obstruction of smaller blood vessels that can cause tissue ischemia and end-organ damage. Vasoocclusion can also manifest as acute episodes of severe pain, also known as vasoocclusive crises (VOC); these episodes of severe pain are a hallmark of SCD and can occur at various locations throughout the body (commonly the hands, feet, chest, and back) depending on the site of vasoocclusion.

Sickle cell disease treatment to prevent VOCs
Until fairly recently, hydroxyurea and/or blood transfusion were the only treatment options available for SCD.³ Hydroxyurea is a disease-modifying treatment for SCD that works by increasing production of fetal hemoglobin, which reduces the amount of HbS available to polymerize, thus leading to a reduction in sickling and improvement in anemia.^3,4 Hydroxyurea is generally recommended as a standard of care in most patients ≥ 9 months of age with more severe forms of SCD to reduce the rates of complications (pain crises, acute chest syndrome), reduce the need for blood transfusions, increase hemoglobin levels, and reduce hospitalizations for pain. In 2017, l-glutamine was approved by the US Food and Drug Administration (FDA) as the first new disease-modifying treatment for SCD in over 20 years; approval of 2 additional agents, voxelotor and crizanlizumab, followed shortly thereafter.³ Detailed information on the evidence supporting approval of these therapies can be found in the May 2021 frequently asked question (FAQ) summary, available here.⁵ Autologous stem cell transplantation is a curative option for patients with SCD; however, the use of stem cell transplantation is limited due to a lack of appropriate donors, the risk for morbidity related to the transplant or graft-related complications, and its prohibitive cost.⁶

On December 8, 2023, the FDA approved 2 new gene therapies (Casgevy [exagamglogene autotemcel; exa-cel] and Lyfgenia [lovotibeglogene autotemcel; lovo-cel]) which target SCD at the source by genetically modifying a patient’s own stem cells ex vivo to produce non-sickling forms of hemoglobin, which are then transplanted back into the patient.^7-9 The purpose of this FAQ is to compare these new gene therapies for SCD and describe the evidence supporting their approval.

Gene therapies for sickle cell disease
Both Lyfgenia and Casgevy utilize the patient’s own CD34⁺ hematopoietic stem cells, which are mobilized using plerixafor, collected via apheresis, modified, then administered back into the patient via autologous transplantation.^6,8,9 Casgevy utilizes gene editing via a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) methodology to modify genomic DNA to inactivate the erythroid-specific enhancer of the BCL11A gene, ultimately leading to increased production of fetal hemoglobin once engrafted in the patient. With Lyfgenia, the patient’s stem cells are transduced ex vivo with a BB305 lentiviral vector that houses a modified β-globin gene; once engrafted, this leads to increased production of hemoglobin A^T87Q, which has potent anti-sickling properties.

Product characteristics and considerations
Table 1 provides a comparison of Casgevy and Lyfgenia, which focuses on differences between the 2 products. Both agents are approved for treatment of patients ≥12 years of age with SCD who have experienced VOCs; Casgevy received additional approval in January 2024 for treatment of patients ≥12 years with transfusion-dependent β-thalassemia.^8,9 Preparation and administration of these agents is quite complex; refer to the prescribing information for each individual product for specific instructions on this process.

Clinical efficacy of gene therapies for sickle cell disease
Lyfgenia
Approval of Lyfgenia was based on a nonrandomized, open-label, multicenter phase1/2 clinical trial (HGB-206), which included patients between 12 and 50 years of age with severe SCD and a documented genotype of β^S/β^S, β^S/β⁰, or β^S/β⁺, a history of failure of hydroxyurea, no more than moderate functional impairment, evidence of active treatment of SCD in the past 24 months, and ineligibility for a matched human leukocyte antigen (HLA) hematopoietic stem cell donation.¹⁰ The trial evaluated 3 separate groups of patients who received sequential treatment with Lyfgenia (Groups A, B, and C). Nine patients were initially enrolled in Groups A (n=7) and B (n=2) to optimize the manufacturing and administration of Lyfgenia.¹¹ Thirty-five patients were subsequently enrolled in Group C; these patients were administered Lyfgenia in a manner consistent with how the drug is currently approved.¹⁰ During the study course, the protocol was further amended to require a history of at least 4 severe VOCs in the 24 months before enrollment.

The primary outcome evaluated in the study was complete resolution of severe VOCs measured between 6 months and 18 months following infusion of Lyfgenia; in the study, a severe VOC was defined as an event resulting in the need for care for ≥24 hours in a hospital or emergency department, ≥2 visits per day to such facilities with requirement for intravenous treatment within a 72-hour period, or priapism lasting ≥2 hours and requiring a visit to a medical facility.¹⁰ The primary outcome was evaluated specifically among patients who met the updated inclusion criterion of having ≥4 severe VOCs prior to enrollment. Secondary outcomes evaluated changes in hemoglobin and other markers of hemolysis; these outcomes were evaluated in all patients who received Lyfgenia.

In an interim analysis conducted in February 2021, 35 patients in Group C (median age, 24 years, 37% female, all with the β^S/β^S genotype) had received treatment with Lyfgenia with a median of 17.3 months of follow-up.¹⁰ Prior to enrollment in the study, these patients had a median of 3 severe VOCs per year and 14% of patients had a history of overt stroke. Patients in Group C received a median of 2 mobilization cycles and a median total dose of 6.9×10⁶ cells/kg body weight of CD34⁺ cells; 80% of the CD34+ cells were positive for the BB305 lentiviral vector. Among the 25 transplant patients with ≥4 VOC in the 24 months prior to enrollment, no patients experienced severe VOCs following infusion of Lyfgenia (compared to a median of 3.5 severe VOCs per year prior to enrollment). In the larger population, hemoglobin levels increased from a median of 8.5 g/dL at baseline to ≥11 g/dL at the 6-month mark; these levels were sustained through 36 months. Other markers of hemolysis that were assessed (eg, lactate dehydrogenase, indirect bilirubin) were generally within normal limits at 6 months and beyond.

Neutrophil and platelet engraftment occurred at a median of 20 days and 36 days, respectively.¹⁰ Following infusion of Lyfgenia, 12 patients (34%) experienced ≥1 serious adverse event (AE), 3 of whom had AEs attributed to treatment, including: grade 2 leukopenia (possibly related), grade 1 decrease in diastolic blood pressure (possibly related), and grade 2 febrile neutropenia (definitely related). All 3 of these AEs resolved within a week of onset. One patient died of cardiac arrest at 20 months following treatment; this patient had severe SCD with a history of pulmonary hypertension and venous thrombosis at baseline, and their death was associated with cardiac fibrosis and chronic cardiopulmonary injury. No cases of hematologic malignancy were observed during the interim follow-up period.

Casgevy
Results of Casgevy’s clinical trial have not yet been published. According to the drug’s prescribing information, the trial (CLIMB-SCD-121) enrolled 63 adult and adolescent patients with SCD and a history of ≥2 severe VOCs (defined as acute pain requiring medical treatment with pain medications or red blood cell transfusion; acute chest syndrome; priapism lasting >2 hours requiring a medical facility visit; or splenic sequestration) in the 2 years prior to enrollment; of these, 44 patients received an infusion of Casgevy.⁸ The primary outcome evaluated was the proportion of VF12 responders, defined as patients with no protocol-defined severe VOCs for ≥12 consecutive months within the first 24 months following infusion of Casgevy. The proportion of patients without hospitalization for severe VOCs during the same time frame (HF12 response) was also evaluated. Enrolled patients had a median age of 20 years, 45% were female, and 91% had a β^S/β^S genotype. In the 2 years prior to enrollment, patients had a median of 3.5 severe VOCs and 2.5 hospitalizations due to severe VOCs per year. In an interim analysis conducted in June 2023, which included a subset of 31 patients with a median follow-up of 22.2 months, 29 patients were VF12 responders (93.5%; 95% CI, 77.9%-100%). None of these 29 patients experienced severe VOCs during the 22.2-month follow-up period. Of 30 patients evaluable for hospitalizations, 100% were without hospitalizations for severe VOCs during the specified time frame.

Additional considerations
While the preparation and administration of Casgevy and Lyfgenia is similar, there are several differences (as highlighted in the Table) which may aid in the selection of therapy for appropriate patients. Notably, Lyfgenia has a boxed warning for risk for development of hematologic malignancy based on 2 patients in HGB-206 who developed and subsequently died from acute myeloid leukemia after receiving Lyfgenia.⁹ The drugs work by different gene editing mechanisms; Casgevy is the first gene therapy approved in the United States that utilizes CRISPR/Cas9 technology.⁷ The FDA recommends that all manufacturers of gene therapy products observe subjects for up to 15 years following administration of therapy to observe for delayed AE; this additional follow-up will be vital to help determine long-term implications of administration of these therapies.¹² Cost of these therapies will also be an important consideration when determining their utility in clinical practice.

In 2023, the Institute for Clinical and Economic Review (ICER) published a cost effectiveness analysis comparing Casgevy and Lyfgenia to standard of care treatment for SCD in adolescents and adults with severe disease who do not have an appropriate donor for hematopoietic stem cell transplantation (HSCT) or who are too old for HSCT.¹³ The analysis utilized a placeholder cost of therapy for both agents of \$2 million based on analyst estimates (since pricing for the agents was not available at the time of analysis) and ultimately found both agents to have the same cost per quality-adjusted life year (QALY) gained: \$193,000 from the health care system perspective and \$162,000 from a modified societal perspective. The report ultimately determined that a health benefit price benchmark for both drugs ranging between \$1.35 million and \$2.05 million would achieve incremental cost-effectiveness ratios between \$100,000 and \$150,000 per QALY gained.

Conclusion
Casgevy and Lyfgenia are the first gene therapies approved for the treatment of adult and adolescent patients with severe SCD in the United States. In interim analyses of their respective clinical trials, both drugs were found to be effective in eliminating occurrence of severe VOCs following administration. While these drugs have the potential to greatly improve the lives of patients suffering from SCD and experiencing VOCs, their long-term effectiveness, safety, and cost will be important considerations when determining their place in therapy.

References

1. Data & statistics on sickle cell disease. Centers for Disease Control and Prevention. Updated July 6, 2023. Accessed January 19, 2024. https://www.cdc.gov/ncbddd/sicklecell/data.html
2. Steinberg MH. Disorders of hemoglobin. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison’s Principles of Internal Medicine, 21^st edition. McGraw-Hill Education; 2022. Accessed January 24, 2024. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3095§ionid=265476010
3. Kavanagh PL, Fasipe TA, Wun T. Sickle cell disease: a review. JAMA. 2022;328(1):57-68. doi:10.1001/jama.2022.10233
4. Evidence-based management of sickle cell disease. National Heart, Lung, and Blood Institute. 2014. Accessed January 24, 2024. https://www.nhlbi.nih.gov/sites/default/files/media/docs/sickle-cell-disease-report%20020816_0.pdf
5. Spencer S. What evidence supports new disease-modifying drug therapies in sickle cell disease? University of Illinois at Chicago Drug Information Group. Published May 2021. Accessed January 24, 2024. https://dig.pharmacy.uic.edu/faqs/2021-2/may-2021-faqs/what-evidence-supports-new-disease-modifying-drug-therapies-in-sickle-cell-disease/
6. Ware RE, Quinn CT. The bold promise of gene therapy for sickle cell disease. Br J Haematol. Published online January 21, 2024. doi:10.1111/bjh.19296
7. FDA approves first gene therapies to treat patients with sickle cell disease. U.S. Food and Drug Administration. Published December 8, 2023. Accessed January 24, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
8. Casgevy. Package insert. Vertex Pharmaceuticals, Inc; 2024.
9. Lyfgenia. Package insert. Bluebird Bio, Inc.; 2023.
10. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clinical efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386(7):617-628. doi:10.1056/NEJMoa2117175
11. Kanter J, Thompson AA, Pierciey FJ Jr, et al. Lovo-cel gene therapy for sickle cell disease: Treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023;98(1):11-22. doi:10.1002/ajh.26741
12. Long term follow-up after administration of human gene therapy products: guidance for industry. Food and Drug Administration. Published January 2020. Accessed January 29, 2024. https://www.fda.gov/media/113768/download
13. Beaudoin F, Thokala P, Nikitin D, et al. Gene therapies for sickle cell disease: effectiveness and value; evidence report. Institute for Clinical and Economic Review. August 21, 2023. Accessed January 29, 2024. https://icer.org/assessment/sickle-cell-disease-2023/

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2024

The information presented is current as of January 18, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.