Exa-cel and Lovo-cel Provide Potential Functional Cure for Patients with SCD or TDT

Sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT) are both hereditary hemoglobinopathies characterized by abnormal hemoglobin production.^1,2 SCD is caused by a mutation in the beta-globin gene leading to the production of hemoglobin S (HbS). When deoxygenated, HbS polymerizes and erythrocytes assume a sickled shape, leading to vaso-occlusion, hemolysis, and ischemic organ damage. Approximately 100,000 people in the United States have SCD.¹

TDT arises from mutations that reduce or abolish beta-globin chain synthesis, resulting in ineffective erythropoiesis and chronic hemolytic anemia. Patients with TDT are dependent on regular blood transfusions for survival; however, this can lead to iron overload and associated complications.²

The burden of these diseases is profound, both in terms of morbidity and mortality and the impact on quality of life.^1,3-5 Patients with SCD frequently experience severe pain, pulmonary hypertension, and organ damage, and they are at increased risk for infections and acute chest syndrome.^1,3 Patients with TDT can experience cardiac complications, cirrhosis, and multiple endocrine abnormalities due to iron overload.^1-3 Furthermore, the disease burden leads to substantial healthcare utilization and costs.^5-8 A recent study of the economic and clinical burden of managing SCD in the United States showed that patients with recurrent vaso-occlusive crises (VOCs) have an average of 2.7 inpatient admissions and 5.0 emergency department visits per patient each year. The lifetime healthcare costs for a patient with SCD with recurrent VOCs is an estimated $3.8 million.⁹

Despite advances in care, there remains a significant unmet medical need for more effective, less burdensome, and curative therapies, highlighting the necessity for ongoing research and development in this field. On December 8, 2023, the US Food and Drug Administration (FDA) approved exagamglogene autotemcel (exa-cel; Casgevy, Vertex Pharmaceuticals Inc.) and lovotibeglogene autotemcel (lovo-cel; Lyfgenia, Bluebird Bio Inc.) for the treatment of SCD in patients aged ≥12 years with a history of recurrent VOCs.^10-12 Exa-cel and lovo-cel are the first cell-based gene therapies approved for the treatment of SCD, and both treatments possess the potential for being long-term and possibly curative.

Vaso-occlusive Crises in SCD Patients

VOCs are a hallmark complication in patients with SCD, significantly impacting morbidity and quality of life.¹³ These crises occur when deformed, sickle-shaped red blood cells obstruct microcirculation, leading to ischemic injury and acute pain episodes. The pathophysiology of VOCs is complex, involving red blood cell sickling, endothelial dysfunction, increased blood viscosity, and inflammation.^13,14

VOCs manifest as excruciating pain episodes, often requiring opioid analgesia.^1,14 The frequency and severity of these crises vary widely among patients.¹⁵ Complications from repeated VOCs include chronic pain syndromes, organ damage (such as splenic sequestration and pulmonary hypertension), and an increased risk of stroke.^1,7,16 The unpredictability of these crises adds to the psychological burden and reduces thFe quality of life for these patients.⁵

In patients with SCD, VOCs are the most common cause of acute hospital admissions, accounting for approximately 95% of hospital admissions of SCD patients.^14,17 The burden of VOCs on the healthcare system is significant, accounting for a substantial portion of the direct medical costs associated with SCD, with inpatient costs being the primary expense. Annually, a patient with SCD incurs, on average, between $6636 and $63,436 more in inpatient costs compared with a patient without SCD.¹⁸ Moreover, the recurrent nature of VOCs leads to repeated hospitalizations, contributing to the high healthcare utilization in this patient population.^17,19 Effective management of VOCs, therefore, remains a critical aspect of improving quality of life and reducing healthcare resource utilization in patients with SCD.

Current Disease Management of SCD and TDT

In the management of SCD, treatment of VOCs involves symptom management, including pain control and hydration.¹³ In addition to pain management, disease-modifying therapies should be offered to patients who have active disease or progressive end-organ damage. These therapies, such as hydroxyurea, voxelotor, and crizanlizumab, help preserve organ function and improve quality of life.²⁰ Hydroxyurea, a first-line therapy, enhances fetal hemoglobin (HbF) production, thereby reducing the frequency of crises. However, its effectiveness varies, and it is not a cure, and hydroxyurea requires frequent monitoring. Side effects include hair loss, nail-bed color changes, and gastrointestinal distress.¹³ Newer agents such as voxelotor, targeting hemoglobin polymerization, and crizanlizumab, which inhibits cell adhesion, offer additional therapeutic options but are not curative.²¹ Despite these advancements, managing VOCs remains complex due to the challenges associated with pain control, the necessity for individualized treatment approaches, and the risks associated with regular blood transfusions, including iron overload and alloimmunization.

In TDT, the standard of care involves regular lifelong blood transfusions coupled with iron chelation therapy to combat iron overload. These treatments, though lifesaving, come with significant limitations, including side effects, variable patient response, and significant treatment burden, which impact patient quality of life. Hematopoietic stem-cell transplantation, the only potentially curative option, is limited by donor availability, risks of graft-versus-host disease, and intensive procedure demands.²

Gene Therapy for Hematologic Disorders

Gene therapy represents a revolutionary approach in treating hematologic disorders, offering the potential for long-term, curative treatments. Gene therapy involves introducing genetic material into a patient’s cells to compensate for abnormal genes or to make a beneficial protein. Its application in hematologic disorders leverages the ability to modify genes in hematopoietic stem cells (HSCs), potentially correcting disorders at their root cause. Unfortunately, HSC transplantation has a 5% to 10% mortality rate, and only approximately 15% of patients are matched with a donor.²²

In the context of hematologic disorders, gene therapy has evolved significantly. Early trials in the 1990s focused on monogenic diseases, such as severe combined immunodeficiency, but these therapies had challenges including gene transfer efficiency and safety concerns.²³ The advent of advanced techniques, such as lentiviral vectors and CRISPR-Cas9 gene editing, has propelled gene therapy forward.^22,24

For SCD and TDT, recent genome-wide–association studies have associated a link between the BCL11A gene on chromosome 2 and increased HbF. Particularly, the ‘C’ allele of the single-nucleotide polymorphism rs11886868 within BCL11A is notably associated with higher HbF levels, as evidenced by its higher frequency in thalassemia patients and its strong correlation with increased HbF in SCD patients (P<10^˜20). Downregulation of BCL11A can increase expression of HbF. These findings suggest the potential of targeting BCL11A in therapies aimed at increasing HbF levels, thereby mitigating the severity of SCD and TDT.^25,26

Gene therapy that induces the production of HbF can ameliorate the clinical severity of SCD and TDT. This approach has evolved from a high-risk experimental procedure to a more feasible and potentially life-altering treatment, reflecting the remarkable progress in the field of gene therapy for hematologic disorders.

Potentially Transformative Role of Exa-cel in SCD and TDT Treatment

Exa-cel, previously referred to as CTX001, represents a transformative approach in the treatment landscape of SCD and TDT. Using CRISPR-Cas9 genome-editing technology, exa-cel precisely modifies the BCL11A gene in HSCs to reactivate HbF production, ameliorating the defective hemoglobin characteristic of both SCD and TDT. In SCD, increased HbF levels replace HbS, reducing cell sickling, hemolysis, and VOCs. In TDT, enhanced HbF production compensates for the beta-globin deficiency, improving anemia and reducing transfusion requirements.^11,24,25,27

The CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) clinical trials assessed the efficacy of exa-cel in patients aged 12 to 35 years with TDT or SCD, respectively.^25,27 The phase 1/2 trial CLIMB THAL-111 showed significant increases in HbF levels post-treatment in patients with TDT, leading to marked decreases or complete cessation of transfusion needs.²⁵ In fact, 88.9% of participants achieved the primary end point of transfusion independence for ≥12 consecutive months.^27,28 Moreover, indices of hemolysis returned to normal levels after treatment.²⁵

In the CLIMB SCD-121 trial, HbF and total hemoglobin levels increased in SCD patients after exa-cel therapy, with reports of >99% of F-cell expression within 6 months of treatment.^25,27 In addition, 94.1% of participants reported freedom from VOCs, and none of the SCD patients receiving exa-cel were hospitalized from VOCs for ≥12 consecutive months (P<.0001).²⁷ Through follow-up to 43.7 months, the mean HbF was maintained at approximately 40.0%, with pancellular distribution. Moreover, the modified BCL11A gene level was stable in both the bone marrow and peripheral blood.²⁷ These results underscore exa-cel’s potential to significantly alter disease progression and enhance patient outcomes.

Safety and efficacy data for exa-cel have been promising. Common side effects align with those associated with autologous stem-cell transplantation, and patients had evidence of neutrophil and platelet engraftment after weeks of therapy. For the SCD clinical trial, no serious adverse events (SAEs) related to exa-cel were reported. In all, 2 patients with TDT experienced SAEs attributed to exa-cel treatment, including hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, headache, thrombocytopenia, and delayed engraftment, but these SAEs were later resolved.^27,28

For decades, the management of SCD and TDT was primarily supportive. Exa-cel’s capacity to address the genetic underpinnings of these diseases heralds a new frontier in treatment, moving from symptomatic relief to targeting the root cause. This paradigm shift may redefine the management of these conditions from chronic, debilitating diseases to potentially curable diseases.

According to Franco Locatelli, MD, PhD, Professor of Pediatrics at the Sapienza University of Rome, Director of the Department of Pediatric Hematology and Oncology at Bambino Gesù Children’s Hospital, “This analysis confirms the potential of exa-cel to render patients transfusion-independent or VOC-free, with significant improvement in their quality of life and physical performance. This therapy offers the potential of a functional cure for patients with transfusion-dependent beta thalassemia or severe SCD along with a favorable safety profile.”²⁸

Lovo-cel as a Potential Treatment of SCD

Lovo-cel is another promising gene therapy treatment of SCD. Lovo-cel gene therapy offers an alternative approach to allogeneic transplantation and is administered via autologous hematopoietic stem and progenitor cell (HSPC) transplantation. The therapy involves transducing autologous HSPCs with the BB305 lentiviral vector that carries a modified beta-globin gene.²⁹

This modification incorporates a specific amino acid change—threonine to glutamine at position 87 (T87Q)—in adult hemoglobin (HbA) to produce an antisickling hemoglobin, HbA^T87Q. This single substitution is designed to hinder the expression and polymerization of HbS, a key factor in SCD, while maintaining the normal morphology and function of HbA. It is important to note that lovo-cel’s use of autologous transplantation addresses 2 major challenges associated with allogeneic transplantation: graft-versus-host disease and graft rejection. By circumventing the need for a matched donor, lovo-cel emerges as a potentially curative treatment for SCD.²⁹

The phase 1/2, open-label, single-dose clinical trial HGB-206 (NCT02140554) evaluated the safety and efficacy of lovo-cel for the treatment of SCD across 11 different sites in the United States.²⁹ Eligible patients were aged 12 to 50 years with an SCD diagnosis who received active treatment in the prior 2 years. In addition, eligible patients must also have prior hydroxyurea intolerance or nonresponse.³⁰

Of the patients included in the study, 88% (28/32) achieved complete resolution of VOCs between 6 and 18 months after treatment, and 94% (30/32) achieved complete resolution of severe VOCs.¹² Similarly, 86% of patients achieved globin response where HbA^T87Q comprised at least 30% of the total hemoglobin concentration, and the total hemoglobin concentration increased compared with baseline. All patients who achieved globin response maintained it throughout the study duration.¹²

Throughout the study period, extending up to 36 months, the vector copy number in the patients’ peripheral blood consistently remained stable from 6 months post-infusion to their last visit. This stability indicates the ongoing presence and effectiveness of vector-positive, long-term repopulating HSPCs. These cells are crucial for maintaining the continuous production of red blood cells and the antisickling hemoglobin HbA^T87Q.³⁰

The most common grade ≥3 adverse reactions with an incidence ≥20% were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia.¹² In all, 2 patients in the initial lovo-cel clinical trial developed acute myeloid leukemia unlikely related to insertional oncogenesis.²⁹ On approval, however, the FDA did issue a boxed warning stating that hematologic malignancy has occurred in patients treated with lovo-cel. Thus, patients must be monitored closely for evidence of malignancy via complete blood counts at least every 6 months.¹²

According to John F. Tisdale, MD, Chief, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, “Sickle cell is a complex and often misunderstood disease that is associated with more symptoms and long-term effects than pain alone. It is encouraging to see that the [lovo-cel] treatment fundamentally impacted the pathophysiology of patients’ disease through the sustained production of vector-derived antisickling hemoglobin to substantially reduce sickling and hemolysis.”³¹

Potential Economic Costs of Exa-cel and Lovo-cel

Following FDA approval, the manufacturers of exa-cel and lovo-cel announced their list prices for treating SCD in the United States: $2.2 million for exa-cel and $3.1 million for lovo-cel.³² The Institute for Clinical and Economic Review (ICER) evaluated the Health Benefit Price Benchmark (HBPB) for the annual cost of treatment with either exa-cel or lovo-cel. HBPBs were established based on the range within which a drug achieves incremental cost-effectiveness ratios of $100,000 to $150,000 per quality-adjusted life-year or per equal value life-year gained. In this analysis, ICER adopted a dual perspective approach, encompassing both the healthcare system perspective and a modified societal perspective, thereby forming a co-base–case scenario. ICER calculated that HBPBs for lovo-cel and exa-cel span a range from $1.35 million to $2.05 million.³³

Conclusion

The development and clinical trial outcomes of exa-cel and lovo-cel represent a major advancement in the field of gene therapy, offering hope for a substantial improvement in the quality-of-life and long-term outcomes for patients with SCD and TDT. Although long-term efficacy and safety data for each therapy are still forthcoming with ongoing long-term studies, such as the 15-year follow-up CLIMB-131 trial,^10,27 the current evidence positions exa-cel and lovo-cel as highly promising therapeutic options. Unlike allogeneic HSC-based therapies, where up to 85% of patients are not matched to a donor, both exa-cel and lovo-cel use the patient’s own HSCs to produce the therapy, avoiding graft-versus-host disease and graft rejection.^10,24,27,29 This progress is a testament to the evolving landscape of medical science, moving us closer to achieving lasting cures for these historically challenging conditions. The ongoing research and development in this field underscores the importance of continued innovation and exploration in the realm of genetic and cellular therapies for patients with SCD and TDT.

References

1. Kavanagh PL, Fasipe TA, Wun T. Sickle cell disease: a review. JAMA. 2022;328(1):57-68.
2. 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.
3. De A, Williams S, Yao Y, et al. Acute chest syndrome, airway inflammation and lung function in sickle cell disease. PloS One. 2023;18(3):e0283349.
4. Mokhtar GM, Gadallah M, El Sherif NHK, Ali HTA. Morbidities and mortality in transfusion-dependent beta-thalassemia patients (single-center experience). Pediatr Hematol Oncol. 2013;30(2):93-103.
5. Lee S, Vania DK, Bhor M, Revicki D, Abogunrin S, Sarri G. Patient-reported outcomes and economic burden of adults with sickle cell disease in the United States: a systematic review. Int J Gen Med. 2020;13:361-377.
6. Zhen X, Ming J, Zhang R, et al. Economic burden of adult patients with β-thalassaemia major in mainland China. Orphanet J Rare Dis. 2023;18(1):252.
7. Inusa BP, Atoyebi W, Andemariam B, Hourani JN, Omert L. Global burden of transfusion in sickle cell disease. Transfus Apher Sci Off J World Apher Assoc Off J Eur Soc Haemapheresis. Published online July 17, 2023:103764.
8. Lanzkron S, Carroll CP, Haywood C. The burden of emergency department use for sickle-cell disease: an analysis of the national emergency department sample database. Am J Hematol. 2010;85(10):797-799.
9. Udeze C, Evans KA, Yang Y, et al. Economic and clinical burden of managing sickle cell disease with recurrent vaso-occlusive crises in the United States. Adv Ther. 2023;40(8):3543-3558.
10. FDA approves first gene therapies to treat patients with sickle cell disease. U.S. Food & Drug Administration. Published December 8, 2023. Accessed January 2, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
11. CASGEVY (exagamglogene autotemcel), suspension for intravenous infusion [Prescribing Information]. Vertex Pharmaceuticals Inc; 2023. Accessed January 2, 2024. https://www.casgevyhcp.com/sickle-cell-disease/sites/default/files/uspi-ppi_exagamglogene_autotemcel.pdf
12. LYFGENIA (lovotibeglogene autotemcel) suspension for intravenous infusion [Prescribing Information]. Bluebird Bio Inc; 2023. Accessed January 2, 2024. https://www.bluebirdbio.com/-/media/bluebirdbio/Corporate%20COM/Files/Lyfgenia/LYFGENIA_Prescribing_Information.pdf
13. Osunkwo I, Manwani D, Kanter J. Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease. Ther Adv Hematol. 2020;11:2040620720955000.
14. Darbari DS, Sheehan VA, Ballas SK. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management. Eur J Haematol. 2020;105(3):237-246.
15. Zaidi AU, Glaros AK, Lee S, et al. A systematic literature review of frequency of vaso-occlusive crises in sickle cell disease. Orphanet J Rare Dis. 2021;16:460.
16. Ladu AI, Aiyenigba AO, Adekile A, Bates I. The spectrum of splenic complications in patients with sickle cell disease in Africa: a systematic review. Br J Haematol. 2021;193(1):26-42.
17. Ballas SK, Lusardi M. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. Am J Hematol. 2005;79(1):17-25.
18. Baldwin Z, Jiao B, Basu A, et al. Medical and non-medical costs of sickle cell disease and treatments from a US perspective: a systematic review and landscape analysis. PharmacoEconomics - Open. 2022;6(4):469-481.
19. Bailey M, Abioye A, Morgan G, et al. Relationship between vaso-occlusive crises and important complications in sickle cell disease patients. Blood. 2019;134(Suppl_1):2167-2167.
20. Standard of care guidelines for patients with sickle cell disease. University of California, San Francisco Sickle Cell Center of Excellence. Published August 17, 2023. Accessed January 3, 2024. https://ucsf.app.box.com/s/ekyd8ken7ngi7mufxfju0x45xwebtlid
21. Salinas Cisneros G, Thein SL. Recent advances in the treatment of sickle cell disease. Front Physiol. 2020;11:435.
22. Dong AC, Rivella S. Gene addition strategies for β-thalassemia and sickle cell anemia. Adv Exp Med Biol. 2017;1013:155-176.
23. Nienhuis AW. Development of gene therapy for blood disorders: an update. Blood. 2013;122(9):1556-1564.
24. Park SH, Bao G. CRISPR/Cas9 gene editing for curing sickle cell disease. Transfus Apher Sci Off J World Apher Assoc Off J Eur Soc Haemapheresis. 2021;60(1):103060.
25. Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384(3):252-260.
26. Uda M, Galanello R, Sanna S, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proc Natl Acad Sci U S A. 2008;105(5):1620-1625.
27. Positive results from pivotal trials of exa-cel for transfusion-dependent beta thalassemia and severe sickle cell disease presented at the 2023 Annual European Hematology Association (EHA) Congress. CRISPR Therapeutics. Accessed November 10, 2023. http://ir.crisprtx.com/news-releases/news-release-details/positive-results-pivotal-trials-exa-cel-transfusion-dependent/
28. Locatelli F, Lang P, Corbacioglu S, et al. S270: transfusion independence after exagamglogene autotemcel in patients with transfusion-dependent beta-thalassemia. HemaSphere. 2023;7(S3):e8473180.
29. Kanter J, Thompson AA, Pierciey FJ, 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.
30. 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.
31. New and updated data demonstrating sustained treatment response in patients treated in largest sickle cell gene therapy program to-date presented at ASH21 and published in NEJM. Business Wire. Published December 12, 2021. Accessed January 3, 2024. https://www.businesswire.com/news/home/20211212005093/en/New-and-Updated-Data-Demonstrating-Sustained-Treatment-Response-in-Patients-Treated-in-Largest-Sickle-Cell-Gene-Therapy-Program-To-Date-Presented-at-ASH21-and-Published-in-NEJM
32. Vertex/CRISPR price sickle cell disease gene therapy at $2.2 mln. Reuters. Published December 8, 2023. Accessed January 3, 2024. https://www.reuters.com/business/healthcare-pharmaceuticals/vertexcrispr-price-sickle-cell-disease-gene-therapy-22-mln-2023-12-08/
33. 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. Published August 21, 2023. Accessed January 3, 2024. https://icer.org/assessment/sickle-cell-disease-2023/