What information is available on gene therapies for treatment of beta-thalassemia?

Introduction
Thalassemia refers to a heterogenous group of inherited blood diseases characterized by decreased synthesis of alpha or beta chains of hemoglobin (Hb).^1,2 Hemoglobin is the oxygen-carrying component of red blood cells (RBCs) and consists of 2 proteins– an alpha and a beta.² If there is decreased production of either of these 2 proteins, the RBCs do not form correctly and cannot carry adequate oxygen, resulting in anemia that begins in early childhood and remains throughout life. Beta-thalassemia affects millions of people worldwide and is one of the most common genetic anemias.³ In the U.S., the prevalence of beta‐thalassemia has increased approximately 7.5% over the last 5 decades.⁴ Beta‐thalassemia is caused by mutations in the beta-globin gene, resulting in reduced or absent beta-globin protein.³ Ultimately, adult-type Hb deficiency and accumulation of free alpha-globulin leads to intracellular toxicity, hemolysis, and ineffective erythropoiesis. A common clinical consequence is chronic hemolytic anemia.

For years, allogeneic hematopoietic stem cell transplantation has been the only definitive therapy for beta-thalassemia, with a cure achieved in 80% to 90% of patients.¹ Current standards of practice are to offer stem cell transplant early in life, before the development of complications due to iron overload such as cardiovascular disease, liver disease, growth abnormalities, endocrine complications, infectious disease, and bone disease. While stem cell transplantation is the only proven curative treatment, its utility has been limited by the need for a well-matched donor and lifelong immunosuppressive therapy post-transplant.

Medical treatment of beta-thalassemia typically includes RBC transfusions and iron chelation to mitigate the iron overload associated with the RBC transfusions.^1,3 Effective blood transfusions allow for adequate physical growth and development, good energy levels, and sufficient suppression of hematopoiesis.¹ Iron chelation therapy with deferoxamine, deferasirox, or deferiprone is effective in decreasing total body iron burden and liver iron concentration. Newer agents that are targeted toward the underlying pathophysiology have recently become available, including luspatercept (an erythroid maturation agent approved in 2019) and gene therapies. The emergence of gene therapies is particularly exciting since they open a new landscape for treatment. As transplantation is not feasible for most patients with beta-thalassemia, gene therapy aims to provide a cure for the disease through the manipulation of the genome of hematopoietic stem cells.

The first gene therapy for beta-thalassemia, betibeglogene autotemcel (Zynteglo^™), was approved by the U.S. Food and Drug Administration (FDA) in August 2022.⁵ In January 2024, exagamglogene autotemcel (Casgevy^™) became the second cell-based gene therapy approved in the U.S. for beta-thalassemia.⁶ The purpose of this frequently asked question (FAQ) is to compare these gene therapies for beta-thalassemia and describe the evidence supporting their approval. Of note, Casgevy was initially approved in December 2023 for the treatment of sickle cell disease⁶; detailed information on the use of Casgevy for this indication is described separately in the February 2024 FAQ summary, available here.

Guideline recommendations on the management of thalassemia
In 2021, the Thalassaemia International Federation updated its guideline for the management of transfusion-dependent thalassemia.¹ After confirming the diagnosis of thalassemia, RBC transfusion therapy is appropriate for: a) patients with a Hb level 2 weeks apart (excluding all other contributory causes), or b) for patients with a Hb >70 g/L and any of the following clinical criteria: symptomatic anemia, poor growth or failure to thrive, complications from excessive intramedullary hematopoiesis, or clinically significant extramedullary hematopoiesis. When needed, iron chelation therapy improves survival, decreases the risk of heart failure, and decreases morbidity from transfusion-induced iron overload. However, prevention of iron overload is preferred to rescue treatment since iron removal by chelation is a slow process and iron-mediated damage is typically irreversible. Luspatercept can be considered for patients ≥18 years of age who require regular RBC transfusions; the use of luspatercept is not recommended in pediatric patients due to lack of efficacy and safety data. Allogeneic hematopoietic stem cell transplant should be offered at an early age (≤17 years) before complications due to iron overload have developed. At the time of guideline development, the only gene therapy that was available was Zynteglo. Zynteglo is recommended for: a) patients aged 12 to 17 years without a human leukocyte antigen-compatible sibling donor, or for b) patients aged 17 to 55 years without severe comorbidities who are at-risk or unable to undergo allogeneic stem cell transplant but can undergo autologous gene therapy with acceptable risk.

Gene therapies for beta-thalassemia
Both Zynteglo and Casgevy are one-time gene therapies that utilize the patient’s own CD34⁺ hematopoietic stem cells. The patient’s stem cells are mobilized using plerixafor, collected via apheresis, modified, then administered back to the patient via autologous transplantation.^7,8

With Zynteglo, the patient’s stem cells are transduced ex vivo with a BB305 lentiviral vector that carries a modified beta-globin gene (β^A-T87Q-globin).⁷ After infusion, transduced CD34⁺ cells engraft in the bone marrow and differentiate to produce RBCs containing β^A-T87Q-globin, which then pairs with alpha-globin and produces a modified functional HbA (HbA^T87Q). In patients with beta-thalassemia, expression of β^A-T87Q-globin corrects the alpha/beta-globin imbalance in erythroid cells and increases functional HbA and total Hb to normal levels, eliminating the dependence on regular RBC transfusions.

In contrast, Casgevy utilizes gene editing via clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) technology. This technology modifies genomic DNA to inactivate the erythroid-specific enhancer of the BCL11A gene.⁸ Reduced BCL11A expression results in an increase in gamma-globin expression. In patients with transfusion-dependent beta-thalassemia, gamma-globin production improves the imbalance of alpha-globin to non-alpha-globin, leading to improved erythropoiesis and increased total Hb levels, thereby eliminating the dependence on regular RBC transfusions.

Product characteristics and considerations
Table 1 provides a comparison of Zynteglo and Casgevy, which focuses on differences between the 2 products.^7,8 Zynteglo is indicated for the treatment of adult and pediatric patients with beta-thalassemia who require regular RBC transfusions, and Casgevy is approved for the treatment of patients aged ≥12 years with transfusion-dependent beta-thalassemia. Preparation and administration of these agents is quite complex; refer to the prescribing information for each individual product for specific instructions on the process. Both agents are only available at authorized treatment centers.^9,10

Clinical efficacy and safety of the gene therapies for beta-thalassemia
Zynteglo
Approval of Zynteglo was based on 2 ongoing, phase 3, open-label, multicenter, single-arm, 24-month studies (Study 1 [NCT02906202] and Study 2 [NCT03207009]) in patients aged 4 to 34 years with beta-thalassemia requiring regular transfusions.^7,11 Patients enrolled in the trials had a history of transfusions of ≥100 mL/kg/year of packed RBCs or ≥8 transfusions of packed RBCs per year for the prior 2 years. The primary outcome evaluated was the achievement of transfusion independence (TI), which is defined as a weighted average Hb ≥9 g/dL without any packed RBC transfusions for a continuous period of ≥12 months at any time during the study after Zynteglo infusion. Findings of the clinical trials are summarized from the prescribing information; all data below is as of March 2021.^7,12

In Study 1, which included 23 patients, the median age was 15 years, 52% were female, 57% were Asian, and 35% were White.⁷ All patients had a non-β⁰/β⁰ genotype, and the median duration of follow-up was 29.5 months. Twenty-two patients were evaluable for TI, of which 20 (91%; 95% confidence interval [CI], 71% to 99%) achieved TI, with a median weighted average Hb during TI of 11.8 g/dL. As of last follow-up, 13 of the 20 patients who achieved TI were not receiving chelation therapy. In Study 2, which included 18 patients, the median age was 13 years, 56% were male, 56% were White, and 39% were Asian. Twelve patients had a β⁰/β⁰ genotype and 6 had a non-β⁰ /β⁰ genotype. The median duration of follow-up was 24.6 months. Fourteen patients were evaluable for TI, of which 12 (86%; 95% CI, 57% to 98%) achieved TI, with a median weighted average Hb during TI of 10.2 g/dL. As of last follow-up, 7 of the 12 patients who achieved TI were not receiving chelation therapy.

At the last follow-up, all patients from both studies were alive and there were no cases of graft versus-host disease, graft failure, or graft rejection.⁷ All patients from both studies who achieved TI (n=32) maintained it, with a minimum and maximum duration of ongoing TI of 12.5+ to 39.4+ months; median duration of TI was not reached. All 32 patients exhibited durable normal or near-normal total Hb levels with a median unsupported total Hb of 11.4 g/dL (minimum, maximum: 9.5, 14.8) at last follow-up.

The prescribing information reports safety data of the 41 patients from both phase 3 studies who received Zynteglo and were followed for a median for 27.2 months.⁷ Grade 3 or 4 adverse reactions that occurred in ≥50% of these patients included neutropenia (100%), thrombocytopenia (100%), leukopenia (100%), anemia (95%), mucositis (63%), lymphopenia (61%), and febrile neutropenia (51%). As of last-follow up, serious adverse events (AEs) occurred in 37% of patients in the 2 trials; the most common serious AEs (>3%) were pyrexia, thrombocytopenia, liver veno-occlusive disease, febrile neutropenia, neutropenia, and stomatitis.

Following completion of the parent studies, patients were encouraged to enroll in an ongoing long-term follow-up study (NCT02633943) for an additional 13 years.⁷ As of March 2021, 19 out of 23 patients from Study 1, and 10 out of 18 patients from Study 2, have enrolled in the long-term follow-up study.

Casgevy
Clinical data of Casgevy in patients with transfusion-dependent beta-thalassemia have not been published; interim data is summarized in the prescribing information from an ongoing open-label, multicenter, single-arm trial (NCT03655678).⁸ Patients were eligible for the trial if they had a history of requiring ≥100 mL/kg/year or 10 units/year of RBC transfusions in the 2 years prior to enrollment. At the time of the interim analysis conducted in January 2023, a total of 52 adolescent and adult patients (aged ≥12 and ≤35 years) received Casgevy. The primary outcome evaluated was the proportion of patients achieving TI for 12 consecutive months (TI12), defined as maintaining weighted average Hb ≥9 g/dL without RBC transfusions for ≥12 consecutive months any time within the first 24 months after Casgevy infusion, evaluated starting 60 days after the last RBC transfusion for post-transplant support or transfusion-dependent beta-thalassemia disease management.

The interim analysis included 35 patients who had adequate follow-up to evaluate the TI12 responder status, with a median duration of follow-up of 23.8 months.⁸ Among the 35 patients, the median age was 20 years, 18 patients (51.4%) were male, 15 patients (42.9%) were White, and 13 patients (37.1%) were Asian. Twenty patients (57.1%) had a β⁰/β⁰-like phenotype and 15 (42.9%) had a non-β⁰ /β⁰-like genotype. Thirty-two of the 35 patients (91.4%; 98.3% one-sided CI, 75.7% to 100%) achieved TI12. All patients who achieved TI12 maintained it, with a median duration of TI of 20.4 months and normal mean weighted average total Hb levels (mean, 13.1 g/dL). No patients experienced graft failure or graft rejection.

The prescribing information summarizes safety data of the 52 patients who received Casgevy and were followed for a median for 20.4 months.⁸ Grade 3 or 4 adverse reactions that occurred in ≥50% of these patients included neutropenia (100%), thrombocytopenia (100%), leucopenia (98%), anemia (92%), and lymphopenia (79%), mucositis (71%), and febrile neutropenia (54%). Serious AEs after myeloablative conditioning and Casgevy infusion occurred in 33% of patients; the most common serious AEs (≥2 patients) were hypoxia, thrombocytopenia, veno-occlusive liver disease, pneumonia, viral infection, and upper respiratory tract infection.

Patients who complete or discontinue from the trial are invited to enroll in an ongoing, long-term follow-up trial (NCT04208529) that will follow patients for a total of 15 years after Casgevy infusion.⁸

Additional considerations
While the preparation and administration of Zynteglo and Casgevy are similar, there are several differences (as highlighted in Table 1) which may aid in the selection of therapy for appropriate patients. Notably, the agents work by different mechanisms; Casgevy is the first gene therapy approved in the U.S. that utilizes CRISPR/Cas9 technology.¹³ 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 AEs; this additional follow-up will be vital to help determine long-term implications of administration of these therapies.¹⁴

Cost of these therapies will also be an important consideration when determining their utility in clinical practice. The manufacturer set the estimated cost of Zynteglo at \$2.8 million per patient, and estimated that the lifetime cost for regular transfusions is \$6.4 million.¹⁵ An evidence report released by the Institute for Clinical and Economic Review (ICER) in July 2022 reported Zynteglo meets accepted value (cost effectiveness) at a cumulative price of \$2.1 million, with an 80% payback option for patients who do not achieve and maintain TI over a 5-year period.^16,17 With regard to clinical effectiveness, the ICER found that there is adequate evidence to support the net health benefit when Zynteglo is compared to standard clinical management. With Casgevy, the price is set at \$2.2 million by the manufacturer.¹⁸ The ICER has not published an evidence report on Casgevy for the treatment of beta-thalassemia; a cost effectiveness analysis comparing Casgevy and Zynteglo to standard of care treatment for beta-thalassemia is not available to date.

Conclusion
Zynteglo and Casgevy are the first gene therapies approved for the treatment of patients with beta-thalassemia in the U.S. In interim analyses of their respective clinical trials, both agents were shown to achieve TI for a continuous period of 12 months (or longer) in most patients following administration. While these drugs have the potential to greatly improve the lives of patients suffering from beta-thalassemia, their long-term effectiveness, safety, and cost will be important considerations when determining their place in therapy.

References

1. Farmakis D, Porter J, Taher A, Domenica Cappellini M, Angastiniotis M, Eleftheriou A. 2021 Thalassaemia International Federation guidelines for the management of transfusion-dependent thalassemia. Hemasphere. 2022;6(8):e732. doi:10.1097/HS9.0000000000000732
2. Bajwa H, Basit H. Thalassemia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 8, 2023.
3. Christakopoulos GE, Telange R, Yen J, Weiss MJ. Gene therapy and gene editing for β-thalassemia. Hematol Oncol Clin North Am. 2023;37(2):433-447. doi:10.1016/j.hoc.2022.12.012
4. Kattamis A, Forni GL, Aydinok Y, Viprakasit V. Changing patterns in the epidemiology of β-thalassemia. Eur J Haematol. 2020;105(6):692-703. doi:10.1111/ejh.13512
5. US Food and Drug Administration. Zynteglo. September 2022. Accessed February 20, 2024. https://www.fda.gov/vaccines-blood-biologics/zynteglo
6. US Food and Drug Administration. Casgevy. January 2024. Accessed February 20, 2024. https://www.fda.gov/vaccines-blood-biologics/casgevy
7. Zynteglo. Package insert. Bluebird Bio, Inc.; 2022.
8. Casgevy. Package insert. Vertex Pharmaceuticals, Inc; 2024.
9. Zynteglo Treatment Journey. Bluebird bio, Inc. 2023. Accessed February 20, 2024. https://www.zynteglo.com/treatment
10. Casgevy Treatment Journey. Vertex Pharmaceuticals, Inc. 2024. Accessed February 20, 2024. https://www.casgevyhcp.com/treatment-journey?condition=scd
11. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene autotemcel gene therapy for non-β0/β0 genotype β-thalassemia. N Engl J Med. 2022;386(5):415-427. doi:10.1056/NEJMoa2113206
12. Zynteglo Clinical Results. Bluebird bio, Inc. 2023. Accessed February 20, 2024. https://www.zynteglohcp.com/efficacy?gad_source=1&gclid=CjwKCAiA29auBhBxEiwAnKcSqvYyX-B_71nMnMJH4u5oevauXKJ_DiydNlpKdlHLo1mreg4_lx_PQhoC8oYQAvD_BwE
13. FDA approves first gene therapies to treat patients with sickle cell disease. U.S. Food and Drug Administration. Updated December 8, 2023. Accessed February 20, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
14. Long term follow-up after administration of human gene therapy products: guidance for industry. Food and Drug Administration. Published January 2020. Accessed February 20, 2024. https://www.fda.gov/media/113768/download
15. Press Release: Bluebird Bio announces U.S. commercial infrastructure to enable patient access to Zynteglo^®, the first and only FDA-approved gene therapy for people with beta-thalassemia who require regular red blood cell transfusions. Bluebird Bio. Published Aug. 17, 2022. Accessed February 20, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-us-commercial-infrastructure-enable
16. Beaudoin FL, Richardson M, Synnott PG, et al. Betibeglogene autotemcel for beta thalassemia: effectiveness and value; final evidence report. Institute for Clinical and Economic Review. July 19, 2022. Accessed February 20, 2024. https://icer.org/wp-content/uploads/2021/11/ICER_Beta-Thalassemia_Evidence-Report_060222-1.pdf
17. Lancaster V, Richardson M, Beaudoin FL, et al. The effectiveness and value of betibeglogene autotemcel for the management of transfusion-dependent beta-thalassemia. J Manag Care Spec Pharm. 2022;28(11):1316-1320. doi:10.18553/jmcp.2022.28.11.1316
18. Kolata G. FDA approves sickle cell treatments, including one that uses CRISPR. The New York Times. December 8, 2023. Accessed February 20, 2024. https://www.nytimes.com/2023/12/08/health/fda-sickle-cell-crispr.html

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

March 2024

The information presented is current as of February 22, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.