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Casgevy™ (exagamglogene autotemcel)
08.02.14

Policy

MEDICALLY NECESSARY

 

Exagamglogene autotemcel (Casgevy) is considered medically necessary and, therefore, covered for the treatment of the following conditions in individuals aged 12 years and older ​when ALL of the associated criteria for them are met:

 

SEVERE SICKLE CELL DISEASE -- (must meet all): 

  • Individual has diagnosis of severe sickle cell disease (SCD) with one of the following genotypes as confirmed by genetic testing results [(a or b) [see GUIDELINES for additional note]:

a. βS/βS

b. βS/β0


  • Documentation that the individual is a candidate for an allogeneic HSCT, but ineligible due to absence of an appropriate donor (i.e., individual does not have a human leukocyte antigen (HLA)-matched donor; or individual has an HLA-matched donor, but the potential donor is not able or is not willing to donate);
  • Individual has not received a prior allogenic hematopoietic stem cell transplant; 
  • Individual is eligible to receive an autologous hematopoietic stem cell transplant; ​
  • Individual has been treated with at least ONE pharmacologic treatment for SCD (e.g., pharmacologic treatment for SCD including hydroxyurea, L-glutamine, Adakveo (crizanlizumab-tmca intravenous infusion), and Oxbryta [voxelotor tablets and tablets for oral suspension]);
  • ​While receiving appropriate standard treatment for SCD, individual had at least four severe vaso-occlusive crises or events (VOCs/VOEs) in the previous 2 years, which can be defined by one or more of the following (i, ii, iii, iv, or v):

 i. An episode of acute pain that resulted in a visit to a medical facility that required administration of at least ONE of the following (a or b):

a) Intravenous opioid; OR 

b) Intravenous nonsteroidal anti-inflammatory drug;

ii. Acute chest syndrome (acute chest syndrome is defined by the presence of a new pulmonary infiltrate associated with pneumonia-like symptoms (e.g., chest pain, fever [> 99.5°F], tachypnea, wheezing or cough, or findings upon lung auscultation);

iii. Acute hepatic sequestration (defined by a sudden increase in liver size associated with pain in the right upper quadrant, abnormal results of liver function test not due to biliary tract disease, and the reduction of hemoglobin concentration by ≥2 g/dL below the baseline value);

iv. Acute splenic sequestration (defined by an enlarged spleen, left upper quadrant pain, and an acute decrease in hemoglobin concentration of ≥ 2 g/dL below the baseline value); 

v. Acute priapism lasting >2 hours and requiring a visit to a medical facility

  • The gene therapy is prescribed by a hematologist or a stem cell transplant physician; AND
  • Individual has not received any gene therapy and/or is not under consideration for treatment for another gene therapy for SCD.

TRANSFUSION-DEPENDENT β-THALASSEMIA 

Treatment of transfusion-dependent β-thalassemia when ALL of the following criteria are met (must meet ALL):


  • Individual has ONE of the following genotypes as confirmed by genetic testing (i or ii): 

i. Non-β0/β0 genotype (e.g., β0/β+, βE/β0, and β+/β+); OR

ii. β0/β0 genotypes (other examples include β0/β+(IVS-I-110) and β+(IVS-I-110)/β+(IVS-I-110);​

  • Individual is transfusion-dependent, as defined by meeting ONE of the following (i or ii): 
i. Receipt of transfusions of ≥100 mL per kg of body weight of packed red blood cells per year in the previous 2 years; OR 
ii. Receipt of transfusions of ≥10 units of packed red blood cells per year in the previous 2 years; ​


  • Documentation that the individual is a candidate for an allogeneic HSCT, but ineligible due to absence of an appropriate donor (i.e., individual does not have a Human Leukocyte Antigen (HLA)-matched donor; or individual has an HLA-matched donor, but the potential donor is not able or is not willing to donate);  

  • According to the prescribing physician, an autologous hematopoietic stem cell transplantation is appropriate for the individual;

  • Individual has not received a previous allogenic hematopoietic stem cell transplant; AND

  • Individual has not received any gene therapy and/or is not under consideration for treatment for another gene therapy for beta thalassemia.​

NOTE: Evio has been selected by the Company to administer clinical outcomes monitoring for individuals receiving certain high-cost drug therapies. Exagamglogene autotemcel (Casgevy) is included in the portfolio of high-cost drug/biologic therapies for which Evio will be tracking clinical outcomes. If an individual meets all medical policy criteria, the requesting physician and/or individual being treated must agree to providing clinical outcomes data and information via Evio's secure web portal as requested.​​


EXPERIMENTAL/INVESTIGATIONAL

 

All other uses, including when the above criteria are not met, for exagamglogene autotemcel (Casgevy) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

 

REQUIRED DOCUMENTATION


The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

Note: ​additional genotypes may be considered during the clinical​ review process based on phenotypic severity of sickle cell disease (SCD) when ALL of the related medical necessity criteria in the POLICY section above are met. 

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, exagamglogene Autotemcel (Casgevy)  is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met. 


US FOOD AND DRUG ADMINISTRATION (FDA) STATUS​

On December 8, 2023, exagamglogene autotemcel (Casgevy) was approved by the FDA for the treatment of SCD in individuals 12 years and older with recurrent vaso-occlusive crises. On January 16, 2024, the FDA expanded the approved indication to include treatment of individuals age 12 years and older with transfusion-dependent β-thalassemia.​

SICKLE CELL DISEASE
In addition to the Policy Criteria above, the following will be needed for exagamglogene autotemcel (Casgevy)​​:

  • Individual does not have the following (i, ii, iii, and iv):
i. Clinically significant and active bacterial, viral, fungal, or parasitic infection; 
ii. Advanced liver disease (e.g., alanine transaminase > 3 times upper limit of normal; direct bilirubin value > 2.5 times upper limit of normal; baseline prothrombin time (international normalized ratio [INR]) > 1.5 times upper limit of normal; cirrhosis; bridging fibrosis; or active hepatitis);
iii. Severe cerebral vasculopathy as defined by history of untreated Moyamoya disease or presence of Moyamoya disease that puts the individual at risk of bleeding, per the prescribing physician; 
iv. Prior or current malignancy, myeloproliferative disorder, or significant immunodeficiency disorder; 

  • According to the prescribing physician, individual will have been discontinued from the following medications (for the duration noted) [i and ii]:

i. Disease-modifying therapies for SCD for at least 2 months before the planned start of mobilization and conditioning (e.g., disease-modifying therapies for SCD include hydroxyurea, Adakveo, L-glutamine, and Oxbryta).
ii. Iron chelation therapy for at least 7 days prior to myeloablative conditioning (e.g., iron chelators used for this condition include deferoxamine injection, deferiprone tablets or solution, and deferasirox tablets);
  • According to the prescribing physician, individual meets ALL of the following (i, ii, iii, and iv):
i. Individual will undergo mobilization, apheresis, and myeloablative conditioning; 
ii. A hematopoietic stem cell mobilizer will be utilized for mobilization (Mozobil (plerixafor subcutaneous injection) is an example of a hematopoietic stem cell mobilizer);
iii. Busulfan will be used for myeloablative conditioning;
iv. Sickle hemoglobin level will be < 30% of total hemoglobin with total hemoglobin concentration ≤ 11 g/dL at BOTH of the following timepoints (a and b):
a) Prior to planned start of mobilization; 
b) Until initiation of myeloablative conditioning; 
  • Prior to collection of cells for manufacturing, cellular screening is negative for ALL of the following (i, ii, iii, and iv):
i. Human immunodeficiency virus-1 and -2 [documentation required]; AND
ii. Hepatitis B virus (an individual who has been vaccinated against hepatitis B virus (HBV) [HBV surface antibody-positive] who is negative for other markers of prior HBV infection (e.g., negative
for HBV core antibody) is eligible; an individual with past exposure to HBV is also eligible as long as individual is negative for HBV DNA);
iii. Hepatitis C virus;
iv. Human T-lymphotropic virus-1 and -2

TRANSFUSION-DEPENDENT β-THALASSEMIA


In addition to the POLICY CRITERIA above, the following will be needed for exagamglogene autotemcel (Casgevy):

  • Individual meets BOTH of the following (i and ii):

i. Individual has been evaluated for the presence of severe iron overload;  

ii. Individual does not have evidence of severe iron overload (e.g., abnormal myocardial iron results [a T2*-weighted magnetic resonance imaging measurement of myocardial iron of <10 msec]; high liver iron concentration [≥ 15 mg/g]; liver biopsy results suggest abnormalities; or clinical evidence of organ damage [e.g., endocrine comorbidities]);

  • Individual does not currently have an active bacterial, viral, fungal, or parasitic infection; 
  • Individual does not have the following (i and ii): 

i. Prior or current malignancy, myeloproliferative disorder, or significant immunodeficiency disorder (this does not include adequately treated cone biopsied in situ carcinoma of the cervix uteri and basal or squamous cell carcinoma of the skin);  

ii. Advanced liver disease (e.g., alanine transaminase or aspartate transaminase greater than three times upper limit of normal, direct bilirubin value greater than three times upper limit of normal, active hepatitis, extensive bridging fibrosis, or cirrhosis);

  • According to the prescribing physician, individual will have been discontinued from iron chelation therapy for at least 7 days prior to myeloablative conditioning (e.g., iron chelators used for this condition include deferoxamine injection, deferiprone tablets or solution, and deferasirox tablets);
  • According to the prescribing physician, individual meets ALL of the following (i, ii, iii, and iv): 

i. Individual will undergo mobilization, apheresis, and myeloablative conditioning; 

ii. A granulocyte-colony stimulating factor product and a hematopoietic stem cell mobilizer will be utilized for mobilization (Filgrastim products are examples of a granulocyte-colony stimulating factor therapy and Mozobil (plerixafor subcutaneous injection) is an example of a hematopoietic stem cell mobilizer);

iii. Busulfan will be used for myeloablative conditioning; 

iv. Total hemoglobin level is ≥ 11 g/dL at BOTH of the following timepoints (a and b): 

a) Prior to mobilization; 

b) Prior to myeloablative conditioning; 

  • Prior to collection of cells for manufacturing, cellular screening is negative for ALL of the following (i, ii, iii, and iv): 

i. Human immunodeficiency virus-1 and -2 ; 

ii. Hepatitis B virus; 

iii. Hepatitis C virus

iv. Human T-lymphotropic virus-1 and -2; AND 

  • Individual has not had a T2*-weighted magnetic resonance imaging measurement of myocardial iron of less than 10 msec or other evidence of severe iron overload in the opinion of treating physician.
DOSING AND FREQUENCY 

Exagamglogene autotemcel (Casgevy) is given one time (per lifetime) as a single dose, which contains a minimum of 3 ×​ 106 cluster of differentiation 34+ (CD34+) cells per kilogram of body weight.

Description

EXAGAMGLOGENE AUTOTEMCEL (CASGEVY)


Exagamglogene autotemcel (Casgevy), known as exa-cel, is branded as Casgevy (Vertex Pharmaceuticals Incorporated). Exagamglogene autotemcel (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. Exagamglogene autotemcel (Casgevy)​ is intended for a one-time administration via a hematopoietic stem cell transplant (HSCT) procedure where the individual'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 individuals 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 individuals 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 individual 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 exagamglogene autotemcel (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 individual 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 exagamglogene autotemcel (Casgevy) infusion, the individual 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 exagamglogene autotemcel (Casgevy).


Although there are no known contraindications, exagamglogene autotemcel ​(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 exagamglogene autotemcel (Casgevy) infusion and requiring use of unmodified rescue CD34+ cells. In the clinical trial, all treated individuals achieved neutrophil engraftment, and no individuals received rescue CD34+ cells. Longer median platelet engraftment times were observed with exagamglogene autotemcel (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 individuals, 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 individuals with SCD and TDT, and decreased appetite in individuals 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, individuals 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.


TRANSFUSION-DEPENDENT β-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, individuals 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, individuals 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 individuals with TDT.


PEER-REVIEWED LITERATURE

 

SICKLE CELL DISEASE 

On December 8, 2023, the FDA approved exagamglogene autotemcel (Casgevy), a CRISPR/Cas9 genome-edited cell therapy, for the treatment of SCD in individuals 12 years and older with recurrent vaso-occlusive crises (VOCs) who mainly have the βs/βs or βs/β0 genotype, for whom HSCT is appropriate and a human leukocyte antigen matched related hematopoietic stem cell donor is not available (Crisper, 2023; Vertex, 2023b). Exagamglogene autotemcel (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 exagamglogene autotemcel (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 exagamglogene autotemcel (Casgevy) were evaluated in an ongoing single-arm, multi-center trial (ClinicalTrials.gov ID NCT03745287) in adult and adolescent individuals with SCD. Individuals had a history of at least two protocol-defined severe VOCs during each of the two years prior to screening. Individuals with an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor were excluded. Individuals were administered exagamglogene autotemcel (Casgevy) with a median (min, max) dose of 4.0 (2.9, 14.4) × 106 cells/kg as an intravenous infusion. As exagamglogene autotemcel (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 individuals were treated with exagamglogene autotemcel (Casgevy). Of the 31 individuals with sufficient follow-up time to be evaluable, 29 (93.5%) achieved this outcome. All treated individuals achieved successful engraftment with no individuals experiencing graft failure or graft rejection. Individuals 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 exagamglogene autotemcel (Casgevy) infusion. 


Sickle cell disease guidelines have not incorporated gene therapies following their FDA approval. The American Society of Hematology (ASH) released evidence-based recommendations for stem cell transplantation for individuals with sickle cell disease in 2021. ASH notes that it is unclear how gene therapies will affect sickle cell disease outcomes, including organ complications and if broader access to curative therapy will alter the trajectory of sickle cell disease outcomes. ASH notes that while success rates after allogeneic HSCT are increasing, survival rates in individuals receiving disease-modifying medications (e.g., hydroxyurea, L-glutamine, Adakveo, Oxbryta) and supportive care are also improving. More than 90% of individuals who have undergone HSCT (predominantly using HLA identical family donors) have been cured of sickle cell disease, as reported in short-term follow-up. Allogeneic HSCT is an established therapeutic option for individuals with sickle cell disease with a clinical indication and an HLA-identical family donor. However, for the majority of individuals, there are no suitable donors.


TRANSFUSION-DEPENDENT β-THALASSEMIA​  

On January 16, 2024, the FDA approved CRISPR/Cas9 gene-edited cell therapy, exagamglogene autotemcel (Casgevy), for the treatment of TDT in individuals 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 exagamglogene autotemcel (Casgevy) in adult and adolescent individuals with TDT. Individuals 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. Individuals were excluded if they had an available 10/10 human leukocyte antigen matched related hematopoietic stem cell donor. A total of 52 (88%) individuals received exagamglogene autotemcel (Casgevy) infusion (full analysis set) and 35 (67%) individuals 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, individuals underwent RBC transfusions prior to mobilization and apheresis and continued receiving transfusions until the initiation of myeloablative conditioning. Individuals received full myeloablative conditioning with busulfan prior to treatment with exagamglogene autotemcel (Casgevy). An intravenous infusion of exagamglogene autotemcel (Casgevy) was then administered with a median (min, max) dose of 7.5 (3.0, 19.7) × 106 CD34+ cells/kg. Because exagamglogene autotemcel (Casgevy) is an autologous therapy, individuals did not require immunosuppressive agents after initial myeloablative conditioning. After infusion, individuals were followed in Trial 2 for 24 months. The primary endpoint of the study was the proportion of individuals 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 exagamglogene autotemcel (Casgevy) infusion. At the time of the interim analysis, 91.4% (32/35) of individuals were TI12 responders (98.3% one-side CI, 75.7-100). All individuals 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 exagamglogene autotemcel (Casgevy) infusion. Among the 3 individuals 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. Individuals 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 exagamglogene autotemcel (Casgevy) infusion (Vertex, 2024).​


Guidelines have not addressed exagamglogene autotemcel (Casgevy). In 2021, the Thalassaemia International Federation published guidelines for the management of TDT.


  • Chelation therapy was cited as an effective treatment modality in improving survival, decreasing the risk of heart failure, and decreasing morbidities from transfusion-induced iron overload. The optimal chelation regimen should be individualized and will vary among individuals and their clinical status.
  • Allogeneic HSCT should be offered to individuals with beta-thalassemia at an early age, before complications due to iron overload have developed if an HLA-identical sibling is available. In some clinical circumstances, a matched unrelated donor can be adequate.
  • Reblozyl® (luspatercept-aamt subcutaneous injection), an erythroid maturation agent, can be considered for individuals≥ 18 years of age who require regular RBC transfusions.
  • Zynteglo™ (betibeglogene autotemcel intravenous infusion), when available, may be an option for selected patients. Examples include young individuals (12 to 17 years of age) with a β+ genotype who do not have an HLA-compatible sibling donor. Also, Zynteglo can be considered in individuals17 to 55 years of age with a β+ genotype who do not have severe comorbidities and are at risk or ineligible to undergo allogeneic HSCT but can otherwise undergo an autologous gene therapy procedure with an acceptable risk.

SUMMARY 


For individuals who are 12 years and older with sickle cell disease who receive exagamglogene autotemcel (Casgevy), the evidence includes one single-arm prospective study. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related mortality, and treatment-related morbidity. In the pivotal single-arm study CLIMB-121, a total of 44 study participants received a single intravenous infusion of exagamglogene autotemcel. Of the 44 total participants, 31 were evaluable for the primary endpoint. The primary endpoint of proportion of study participants who did not experience any protocol-defined severe VOCs for at least 12 consecutive months within the first 24 months after exagamglogene autotemcel (Casgevy)​ infusion was achieved by 29 of 31 or 93.5% study participants. The key secondary endpoint of proportion of study participants who did not require hospitalization due to severe VOCs for at least 12 consecutive months within the 24-month evaluation period was achieved by 100% or 30 of the 30 evaluable study participants. Safety data includes 44 study participants. The adverse event profile was generally consistent with that expected from busulfan myeloablative conditioning and HSC transplant. Serious adverse reactions after myeloablative conditioning and exagamglogene autotemcel infusion were observed in 45% of study participants. In addition to a limited sample size, the length of follow-up is not long enough to remove uncertainty regarding the durability of effect over a longer time. After the primary evaluation period to last follow-up, one of the 29 study participants who achieved primary endpoint experienced an acute pain episode meeting the definition of a severe VOC at month 22.8 requiring a 5-day hospitalization. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect as well as adverse effects. The limited sample sizes of the studies create uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty remains about the degree of risk of unintended, off-target editing in CD34+cells due to uncommon genetic variants. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that exagamglogene autotemcel will frequently be successful in treating sickle cell disease in at least short-term.


For individuals with TDT who receive exagamglogene autotemcel, the evidence includes 1 single-arm study: Study 111. This study enrolled patients with homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E. Relevant outcomes are change in disease status, quality of life, hospitalizations, medication use, treatment-related morbidity and treatment-related mortality. The single open-label study included a total of 52 individuals who received a single intravenous infusion of exagamglogene autotemcel. Of the 52 participants, 35 participants in whom transfusion independence was evaluable were included in the interim efficacy analysis. Transfusion independence was achieved in 91% (98.3% confidence interval, 75.7% to 100%) of study participants. There is uncertainty regarding the durability of effect over a longer time period. Long-term follow-up (>15 years) is required to establish precision around durability of the treatment effect. The limited sample size creates uncertainty around the estimates of some of the patient-important outcomes, particularly adverse events. Some serious harms are likely rare occurrences and as such may not be observed in trials. While most of the serious adverse events were attributable to known risks associated with myeloablative conditioning, uncertainty still remains about the degree of risk of exagamglogene autotemcel infusion in real-world practice. While no cases of malignancies or unintended, off-target genome editing were reported in the trial participants, off-target editing in an individual’s CD34+ cells cannot be ruled out due to genetic variants especially in the larger, real-world, population.​

References

Adakveo® intravenous injection [prescribing information]. East Hanover, NJ: Novartis; September 2022.


Casgevy™ intravenous infusion [prescribing information]. Waltham, MA: Vertex; January 2024.

Centers for Disease Control and Prevention – Sickle cell disease. Available at: https://www.cdc.gov/ncbddd/sicklecell/index.html. Last reviewed July 6, 2023. Accessed on January 29, 2024.

Droxia® capsules [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; January 2022.

Farmakis D, Porter J, Taher A, et al, for the 2021 TIF Guidelines Taskforce. 2021 Thalassaemia.

International Federation guidelines for the management of transfusion-dependent thalassemia. Hemasphere. 2022;6:8(e732).

Kanter J, Liem RI, Bernaudin F, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5:3668-3689.

Kavanagh PL, Fasipe TA, Wun T. Sickle cell disease: a review. JAMA. 2022;328(1):57-68.

Oxbryta® tablets and tablets for oral suspension [prescribing information]. San Francisco, CA: Global Blood Therapeutics; August 2023.

Piel FB, Steinberg MH. Sickle cell disease. N Engl J Med. 2017;376:1561-1573.

Siklos® tablets [prescribing information]. Bryn Mawr, PA: Medunik; December 2021.

Taher AT, Musallam KM, Cappellini MD, et al. β-thalassemias. N Engl J Med. 2021;384;727-743.

Vertex: Exagamglogene autotemcel (exa-cel) for the treatment of sickle cell disease in individuals 12 years and older with recurrent vaso-occlusive crises. FDA Cellular, Tissue and Gene Therapies Advisory Committee. October 31, 2023.​

Coding

CPT Procedure Code Number(s)
N/A​
ICD - 10 Procedure Code Number(s)
N/A​
ICD - 10 Diagnosis Code Number(s)
D56.1               Beta thalassemia

D57.00             Hb-SS disease with crisis, unspecified

D57.01             Hb-SS disease with acute chest syndrome

D57.02             Hb-SS disease with splenic sequestration

D57.03             Hb-SS disease with cerebral vascular involvement

D57.04             Hb-SS disease with dactylitis

D57.09             Hb-SS disease with crisis with other specified complication

HCPCS Level II Code Number(s)
J3392   Injection, exagamglogene autotemcel, per treatment​
Revenue Code Number(s)
N/A​

Coding and Billing Requirements

Policy History

Revisions From 08.02.14:
01/01/2025
This new policy will become effective 1/1/2025.  

It has been issued to communicate the Company's position on exagamglogene autotemcel (Casgevy™)​​​. ​​

1/1/2025
12/30/2024
08.02.14
Medical Policy Bulletin
Commercial
No