Exagamglogene Autotemcel (Casgevy)

Number: 1052

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses exagamglogene autotemcel (Casgevy) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification

Precertification of exagamglogene autotemcel (Casgevy) is required of all Aetna participating providers and members in applicable plan designs. For precertification of exagamglogene autotemcel (Casgevy), contact National Medical Excellence (NME) at 877-212-8811.  

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes® Gene Based, Cellular and Other Innovative Therapy (GCIT^®) Network. For exagamglogene autotemcel (Casgevy), see Aetna Institutes® GCIT Designated Centers. 

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a hematologist.

2. Criteria for Initial Approval

   Aetna considers a one dose total of exagamglogene autotemcel (Casgevy) medically necessary for the following indications when criteria are met:

   1. Sickle cell disease

      Treatment of sickle cell disease when all of the following criteria are met:

      1. Member is 12 years of age or older; and
      2. Member has a diagnosis of sickle cell disease with one of the following genotypes confirmed by molecular or genetic testing:
         
         
         1. βs/βs
         2. βs/β0
         3. βs/β+; and
      3. Member has a documented history of at least 2 severe vaso-occlusive episodes per year during the previous two years (see Appendix A for examples); and
      4. Member is eligible for a hematopoietic stem cell transplant (HSCT) but is unable to find a human leukocyte antigen (HLA)-matched related donor; and 
      5. Member has not received a prior hematopoietic stem cell transplant (HSCT); and
      6. Member has not received Casgevy or any other gene therapy previously; and
      7. Member meets one of the following:
         
         a. Has experienced, at any time in the past, an inadequate response or intolerance to a trial of hydroxyurea; or
         b. Has a contraindication to hydroxyurea;

   2. Transfusion-dependent beta (β)-thalassemia

      Treatment of transfusion-dependent β-thalassemia when all of the following criteria are met:

      1. Member is 12 years of age or older; and
      2. Member has a diagnosis of transfusion-dependent β-thalassemia with a non-β0/β0 or β0/β0 genotype confirmed via molecular or genetic testing (see Appendix B for examples); and
      3. Member has received at least 100 milliliter per kilogram or 10 units of packed red blood cells (pRBCs) per year during the previous two years; and
      4. Member is eligible for a hematopoietic stem cell transplant (HSCT) but is unable to find a human leukocyte antigen (HLA)-matched related donor; and
      5. Member has not received a prior hematopoietic stem cell transplant (HSCT); and
      6. Member has not received Casgevy or any other gene therapy previously.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Related Policies 

   1. CPB 0626 - Hematopoietic Cell Transplantation for Thalassemia Major and Sickle Cell Anemia
   2. CPB 0963 - Luspatercept-aamt (Reblozyl)
   3. CPB 0964 - Crizanlizumab-tmca (Adakveo)
   4. CPB 1016 - Betibeglogene Autotemcel (Zynteglo)
   5. CPB 1053 - Lovotibeglogene Autotemcel (Lyfgenia)

Dosage and Administration

Exagamglogene autotemcel is available as Casgevy, a cell suspension for autologous use and administered as a one-time, single dose intravenous infusion. 

• Individuals are required to undergo hematopoietic stem cell (HSC) mobilization followed by apheresis to obtain CD34+ cells for Casgevy manufacturing.
• Dosing of Casgevy is based on body weight. The minimum recommended dose of Casgevy is 3 × 10⁶ CD34+ cells per kg of body weight, which may be composed of multiple vials. 
• Full myeloablative conditioning must be administered between 48 hours and 7 days before infusion of Casgevy.
• Prophylaxis for seizures should be considered prior to initiating myeloablative conditioning.
• Each vial of Casgevy is administered via intravenous infusion within 20 minutes of thaw.
• For additional information, refer to the Full Prescribing Information for Casgevy.

Source: Vertex Pharmaceuticals, 2024

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion, for therapy, prophylaxis, or diagnosis
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J3392	Injection, exagamglogene autotemcel, per treatment [effective 01/01/25]
Other HCPCS codes related to the CPB:
S0176	Hydroxyurea, oral, 500 mg
ICD-10 codes covered if selection criteria are met:
D56.1	Beta thalassemia
D57.00 – D57.09, D57.1	Sickle-cell disorders

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Casgevy is indicated for the treatment of sickle cell disease (SCD) in patients 12 years and older with recurrent vaso-occlusive crises (VOCs).
• Casgevy is indicated for the treatment of transfusion-dependent beta (β)-thalassemia (TDT) in patients 12 years and older.

Exagamglogene autotemcel, known as exa-cel, is branded as Casgevy (Vertex Pharmaceuticals Incorporated). Casgevy is a genome-edited cellular therapy consisting of autologous CD34+ hematopoietic stem cells (HSCs) edited by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technology (CRISPR Therapeutics) at the erythroid-specific enhancer region of the BCL11A gene. Casgevy is intended for a one-time administration via a hematopoietic stem cell transplant (HSCT) procedure where the patient’s own CD34+ cells are modified to reduce BCL11A expression in erythroid lineage cells, leading to increased fetal hemoglobin (HbF) production. HbF is the form of the oxygen-carrying hemoglobin that is naturally present during fetal development, which then switches to the adult form of hemoglobin after birth. In patients with severe sickle cell disease (SCD), HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the red blood cells (RBCs) from sickling and thereby eliminating vaso-occlusive crises (VOCs). In patients with transfusion-dependent β-thalassemia (TDT), γ-globin production improves the α-globin to non-α-globin imbalance thereby reducing ineffective erythropoiesis and hemolysis and increasing total hemoglobin levels, addressing the underlying cause of disease, and eliminating the dependence on regular RBC transfusions (Vertex, 2024).

This cell-based gene therapy process requires the patient to undergo CD34+ HSC mobilization (where stem cells are stimulated out of the bone marrow space) followed by apheresis (the procedure used to collect stem cells from the blood) to isolate the CD34+ cells needed for Casgevy manufacturing. The collected cells are modified using CRISPR /Cas9 (a type of genome editing technology that can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut), and then transplanted back into the patient via intravenous infusion where they engraft (attach and multiply) within the bone marrow and increase the production of HbF, a type of hemoglobin that facilitates oxygen delivery. Prior to the Casgevy infusion, the patient will receive full myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells in Casgevy.

Although there are no known contraindications, Casgevy carries labeled warnings and precautions for potential neutrophil engraftment failure, prolonged time to platelet engraftment, hypersensitivity reactions, and off-target genome editing risk. Neutrophil engraftment failure is a potential risk in HSC transplant, defined as not achieving neutrophil engraftment after Casgevy infusion and requiring use of unmodified rescue CD34+ cells. In the clinical trial, all treated patients achieved neutrophil engraftment and no patients received rescue CD34+ cells. Longer median platelet engraftment times were observed with Casgevy treatment compared to allogeneic HSC transplant. There is an increased risk of bleeding until platelet engraftment is achieved. In the clinical trial, there was no association observed between incidence of serious bleeding and time to platelet engraftment. Hypersensitivity reactions, including anaphylaxis can occur due to dimethyl sulfoxide (DMSO) or dextran 40 in the cryopreservative solution. Although off-target genome editing was not observed in the edited CD34+ cells evaluated from healthy donors and patients, the risk of unintended, off-target editing in an individual’s CD34+ cells cannot be ruled out due to genetic variants. The clinical significance of potential off-target editing is unknown (Vertex, 2024). 

The most common Grade 3 or 4 non-laboratory adverse reactions (incidence of 25% or more) include mucositis and febrile neutropenia in patients with SCD and TDT, and decreased appetite in patients with SCD. The most common Grade 3 or 4 laboratory abnormalities (50% or more) include neutropenia, thrombocytopenia, leukopenia, anemia, and lymphopenia.

Sickle Cell Disease

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by the presence of hemoglobin S (HbS), which causes red blood cells (RBCs) to become rigid, sticky and sickle shaped. The hallmarks of SCD are vaso-occlusive crisis (VOC) and hemolytic anemia. VOC (previously called sickle cell crisis) occurs when sickled RBCs obstructs blood flow in the blood vessels causing tissue hypoxia resulting in severe, debilitating pain. In hemolytic anemia, sickled RBCs break down prematurely, leading to anemia. Other vaso-occlusive events (VOEs), or complications associated with SCD, include acute chest syndrome (ACS), avascular necrosis, infection, organ damage, and stroke (not an all-inclusive list).

The exact number of people living with SCD in the United States is unknown. It is estimated that SCD affects approximately 100,000 Americans, predominantly among African Americans, and that about 1 in 13 babies is born with the sickle cell trait. In addition, SCD can occur among Hispanic Americans, which is estimated to occur in 1 out of every 16,300 births (CDC, 2023).

SCD is a disease that worsens over time. Management has included prevention and treatment of pain episodes and other complications (e.g., hydration, temperature regulation, blood transfusions, and pharmacotherapy options such as hydroxyurea, L-glutamine, voxelotor, crizanlizumab, analgesics). Hematopoietic stem cell transplantation (HSCT) is a cure for SCD; however, patients require a relative who is a close genetic match to be a donor to have the best chance for a successful transplant. Gene editing (altering the sequence of an endogenous gene) has been studied for a potential cure of SCD.

On December 8, 2023, the FDA approved Casgevy (exagamglogene autotemcel), a CRISPR/Cas9 genome-edited cell therapy, for the treatment of SCD in patients 12 years and older with recurrent vaso-occlusive crises (VOCs) who have the βs/βs, βs/β0, or βs/β+ genotype, for whom HSCT is appropriate and a human leukocyte antigen matched related hematopoietic stem cell donor is not available (Crisper, 2023; Vertex, 2023b). Casgevy is a one-time therapy that offers the potential of a functional cure for SCD by eliminating severe VOCs and hospitalizations caused by severe VOCs. The administration of Casgevy requires specialized experience in stem cell transplantation; therefore, Vertex is engaging with experienced hospitals to establish a network of independently operated, authorized treatment centers throughout the United States.

The safety and effectiveness of Casgevy were evaluated in an ongoing single-arm, multi-center trial (ClinicalTrials.gov ID NCT03745287) in adult and adolescent patients with SCD. Patients had a history of at least two protocol-defined severe VOCs during each of the two years prior to screening. Patients with an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor were excluded. Patients were administered Casgevy with a median (min, max) dose of 4.0 (2.9, 14.4) × 10⁶ cells/kg as an intravenous infusion. As Casgevy is an autologous therapy, immunosuppressive agents were not required after initial myeloablative conditioning. The primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. A total of 44 patients were treated with Casgevy. Of the 31 patients with sufficient follow-up time to be evaluable, 29 (93.5%) achieved this outcome. All treated patients achieved successful engraftment with no patients experiencing graft failure or graft rejection. Patients who complete or discontinue from the trial are encouraged to enroll in an ongoing long-term follow-up trial (NCT04208529) for additional follow up for a total of 15 years after Casgevy infusion. 

Transfusion-Dependent Beta Thalassemia

Transfusion-dependent beta (β) thalassemia (TDT) (formerly designated as beta thalassemia major, Cooley's anemia, or Mediterranean anemia) is an inherited hemoglobinopathy in which defective globin chain syntheses leads to chronic hemolytic anemia requiring chronic, life-long blood transfusions and iron chelation therapy. If left untreated, or treated inadequately, patients may experience fatigue, shortness of breath, reduced cognition, bone weakening, splenomegaly, and liver and/or heart complications. Children may have reduced activity, growth problems and delayed puberty, hepatosplenomegaly, osteopenia, and cognitive impairment. TDT also carries a higher risk of infections and early death.

Beta thalassemia is considered relatively rare in the United states with incidence of symptomatic cases occurring in approximately 1 in 100,000 individuals in the general population (NORD, 2023).

Allogeneic hematopoietic stem cell transplantation (HSCT) has been a curative option; however, patients require a relative who is a close genetic match (human leukocyte antigen [HLA]-matched related donor) to have the best chance for a successful transplant. CRISPR gene-editing technology has been studied as another treatment option for patients with TDT.

On January 16, 2024, the FDA approved CRISPR/Cas9 gene-edited cell therapy, Casgevy, for the treatment of TDT in patients 12 years and older.

FDA approval was based on an ongoing open-label, multi-center, single-arm trial (Trial 2; NCT03655678) that evaluated the safety and efficacy of Casgevy in adult and adolescent patients with TDT. Patients were eligible for the trial if they had a history of needing at least 100 mL/kg/year or 10 units/year of RBC transfusions in the 2 years prior to enrollment. Patients were excluded if they had an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor. A total of 52 (88%) patients received Casgevy infusion (full analysis set) and 35 (67%) patients had adequate follow-up to allow evaluation of the primary endpoint (primary efficacy set). To maintain a total hemoglobin concentration of at least 11 g/dL, patients underwent RBC transfusions prior to mobilization and apheresis and continued receiving transfusions until the initiation of myeloablative conditioning. Patients received full myeloablative conditioning with busulfan prior to treatment with Casgevy. An intravenous infusion of Casgevy was then administered with a median (min, max) dose of 7.5 (3.0, 19.7) × 106 CD34+ cells/kg. Since Casgevy is an autologous therapy, patients did not require immunosuppressive agents after initial myeloablative conditioning. After infusion, patients were followed in Trial 2 for 24 months. The primary endpoint of the study was the proportion of patients achieving transfusion independence for 12 consecutive months (TI12 responder), defined as maintaining weighted average hemoglobin of at least 9 g/dL, without RBC transfusions for at least 12 consecutive months at any time from 60 days after the last RBC transfusion up to 24 months following Casgevy infusion. At the time of the interim analysis, 91.4% (32/35) of patients were TI12 responders (98.3% one-side CI, 75.7-100). All patients who were transfusion independent responders remained transfusion-independent, with a median duration of transfusion-independence of 20.8 months and normal mean weighted average total hemoglobin levels (13.1 g/dL). The median time to last RBC transfusion for transfusion independent responders was 30 days following Casgevy infusion. Among the 3 patients who did not achieve transfusion independence for 12 consecutive months, reductions in annualized RBC transfusion volume requirements and annualized transfusion frequency were observed when compared with baseline requirements. Patients who completed or discontinued from Trial 2 were encouraged to enroll in Trial 3 (NCT04208529), an ongoing long-term follow-up trial for additional follow-up for a total of 15 years after Casgevy infusion (Vertex, 2024).

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Appendix

Appendix A: Examples of Severe Vaso-Occlusive Events

1. Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or intravenous [IV] non-steroidal anti-inflammatory drugs [NSAIDs]) or RBC transfusions
2. Acute chest syndrome
3. Priapism lasting > 2 hours and requiring a visit to a medical facility
4. Splenic sequestration  
5. Hepatic sequestration

Appendix B: Examples of non-β0/β0 OR β0/β0 genotypes

1. β0/β0
2. β0/β+
3. βE/β0
4. β0/IVS-I-110
5. IVS-I-110/IVS-1-110

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References