Coverage Policy Manual
Policy #: 2024013
Category: Pharmacy
Initiated: May 2024
Last Review: June 2025
  Exagamglogene autotemcel (e.g., Casgevy)
Description:
Sickle cell disease (SCD) is an inherited blood disorder affecting red blood cells (RBCs) and has been part of newborn screening since the mid-1980s. HbS polymerization causes cellular alterations in red blood cell morphology (rigid or sickled RBCs) that have shortened lifespans (16 days vs. 120 days for normal RBCs that are replaced), leading to vaso-occlusion. The acute presentation of SCD is associated with vaso-occlusion resulting in recurrent pain episodes, life-threatening infections as a result of splenic infarction, acute chest syndrome, pulmonary hypertension, stroke, and cumulative multiorgan damage. The major problems caused by SCD are hemolytic anemia from hemolysis of red blood cells and vaso-occlusion. Hydroxyurea is a first-line therapy in the management of individuals with SCD. L-glutamine can be a second-line therapy for individuals in whom treatment with hydroxyurea was not effective or who were intolerant to it. Two other medications include crizanlizumab, approved to reduce the frequency of vaso-occlusive crises in adults and pediatric individuals 16 years of age and older, and voxelotor, approved for the treatment of SCD in adults and pediatric individuals 12 years of age and older. Stem cell transplantation has been a last resort measure for the most severe sickle cell individuals, however long-term outcomes data for SCD individuals who undergo HSCT is still lacking.
 
Beta thalassemia is a hematologic disorder caused by a genetic defect in the HBB gene and characterized by ineffective erythropoiesis, which can lead to fewer RBCs and severe anemia. It varies in severity, with some individuals being dependent on regular RBC transfusions, known as transfusion-dependent beta thalassemia (TDT), and some being non–transfusion-dependent. Approximately 2000 patients in the United States are affected, 1500 of whom are transfusion-dependent. At this time, hematopoietic stem cell transplantation (HSCT) with a human leukocyte antigen (HLA)-matched sibling donor is recommended for patients with TDT, as it is a potentially curative option. Overall disease-free survival is >85% in children and 65% in adults. Both older age and presence of organ toxicity due to iron overload can negatively impact outcomes. Risks related to the stem cells include non-engraftment/graft failure, graft-versus-host disease (GVHD), and mortality. In addition, this treatment requires myeloablative therapy, which carries the risk of infertility and infections, and has a mortality risk as well. Because most individuals do not have a suitable donor, there is a need for additional curative therapies.
 
CRISPR Therapeutics’ and Vertex Pharmaceuticals’ exagamlogene autotemcel (e.g., Casgevy) is a nonviral, ex vivo clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)–based gene-edited cell therapy in which an individual’s own hematopoietic stem and progenitor cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break. Reduced BCL11A expression results in an increase in γ-globin expression and fetal hemoglobin (HbF) protein production in erythroid cells. In individuals with severe sickle cell disease (SCD), HbF expression reduces intracellular hemoglobin S (HbS) concentration, preventing the RBCs from sickling, the underlying cause of disease. In individuals with TDT, γ-globin production improves the alpha-globin to non–alpha-globin imbalance, thereby reducing ineffective erythropoiesis and hemolysis and increasing total Hb levels, addressing the underlying cause of TDT. Exagamlogene autotemcel is administered via IV infusion following myeloablative conditioning. The administration and preparation processes are complex and require hospitalization of the individual. The manufacturer has indicated that the timeframe between autologous cell collection and shipment of genetically modified cells back to the treatment center is up to 6 months.
 
Regulatory Status
 
Exagamlogene autotemcel (e.g., Casgevy) was approved by the U.S. Food and Drug Administration (FDA) on December 8, 2023, for the treatment of sickle cell disease (SCD) in individuals 12 years and older with recurrent vaso-occlusive crises (VOCs).
 
Exagamlogene autotemcel (e.g., Casgevy) was approved by the U.S. Food and Drug Administration (FDA) on January 16, 2024 for the treatment of individuals 12 years of age and older with transfusion-dependent beta-thalassemia.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Prior Approval is required for Exagamglogene autotemcel (e.g., Casgevy).
   
The initial use of this drug requires documentation of direct physician involvement (MD/DO) in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
Approval timeframes may differ for members/participants of Self-Insured plans.
 
Effective June 2025
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Exagamlogene autotemcel (e.g., Casgevy) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
For FDA labeled indications, Exagamlogene autotemcel (e.g., Casgevy) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified in the dosage and administration section.
 
SICKLE CELL DISEASE
 
1. Individual is at least 12 years of age (Casgevy, 2024); AND
2. Individual has a documented diagnosis of sickle cell disease confirmed by testing demonstrating the following (Casgevy, 2024):
a. Homozygous sickle cell disease (e.g., HbSS); OR
b. Heterozygous sickle cell disease (e.g., HbSC, HbSBeta+, HbSBeta0, HbSD, HbSOArab, HbSE); AND
3. Individual has a history of recurrent vaso-occlusive crises (VOCs), as evidenced by greater than or equal to 4 severe VOC(s) in the most recent 24 months (see policy guidelines for a definition of VOC); AND
4. Applicable only to individuals less than 18 years of age: Individual does not have an available and willing matched HLA-identical sibling or haploidentical related hematopoietic cell donor (Frangoul, 2023) (Kassim 2024); AND
5. Individual has not received allogenic hematopoietic stem cell transplant (Casgevy, 2024); AND
6. Individual meets the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see policy guidelines):
a. Adequate Karnofsky performance status or Lansky performance status
b. Absence of advanced liver disease
c. Adequate estimated glomerular filtration rate (eGFR)
d. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO)
e. Adequate left ventricular ejection fraction (LVEF)
f. Absence of clinically significant active infection(s)
7. Individual does not have a history of receiving gene therapy or is not under consideration for treatment with another gene therapy for sickle cell disease.
 
BETA THALASSEMIA
 
1. Individual is at least 12 years of age (Casgevy, 2024); AND
2. Individual has a documented diagnosis of Beta-thalassemia as evidenced by one of the following genotypes by globin gene testing (Casgevy, 2024):
a. Beta0/Beta0; OR
b. Beta0/Beta0 – like (see policy guidelines); OR
c. Non-Beta0/Beta0 (see policy guidelines); AND
3. Individual requires regular peripheral blood transfusions to maintain target hemoglobin levels as defined by documentation of the following:
a. History of receiving transfusions of greater than or equal to 100 ml per kilogram of body weight of packed red blood cells per year; OR
b. History of receiving greater than or equal to 8 transfusions per year in the prior 2 years at the time of treatment decision (Frangoul, 2023; Locatelli, 2022); AND
4. Applicable only to individuals less than 18 years of age: Individual does not have an available and willing matched HLA-identical sibling or haploidentical related hematopoietic cell donor (Frangoul, 2023) (Kassim 2024); AND
5. Individual has not received allogenic hematopoietic stem cell transplant (Casgevy, 2024); AND
6. Individual meets the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see policy guidelines):
a. Adequate Karnofsky performance status or Lansky performance status
b. Absence of advanced liver disease
c. Adequate estimated glomerular filtration rate (eGFR)
d. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO)
e. Adequate left ventricular ejection fraction (LVEF)
f. Absence of clinically significant active infection(s)
7. Individual does not have a history of receiving gene therapy or is not under consideration for treatment with another gene therapy for beta thalassemia.
 
Policy guidelines
 
VOC is defined as either:
 
1. Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or IV NSAIDs) or RBC transfusions; OR
2. Acute chest syndrome; OR
3. Priapism lasting greater than 2 hours and requiring a visit to a medical facility; OR
4. Acute hepatic sequestration; OR
5. Acute splenic sequestration (Frangoul 2023, Kanter 2022, Lowe 2023).
 
Examples of beta thalassemia genotypes
 
1. Beta0/Beta0 – like:
a. Beta0/Beta+ (IVS-I-110)
b. Beta+ (IVS-I-110)/Beta+ (IVS-I-110)
2. Non-Beta0/Beta0:
a. Beta0/Beta+
b. BetaE/Beta0
c. Beta+/Beta+    
 
Institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy may include:
 
1. Adequate cell counts defined as WBC 3,000/mcL or more, ANC 1,000/mcL or more (greater than or equal to 500/mcL for those on hydroxyurea treatment) or platelets greater than or equal to 50,000-100,000/mcL
2. Adequate heart function defined as LVEF greater than or equal to 45% or cardiac T2* greater than or equal to 10 ms.
3. Absence of advanced liver disease (defined as ALT greater than 3x ULN, AST greater than or equal to 3x ULN, direct bilirubin value greater than 2x ULN, PT INR greater than or equal to 1.5x ULN, history of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy)
4. Adequate lung function defined as DLCO greater than or equal to 50% of predicted value and baseline oxygen saturation greater than or equal to 90% without supplemental oxygen
5. Adequate performance status defined as Karnofsky performance status greater than 60 (16 years of age or older) or Lansky performance status greater than 60 (less than 16 years of age)
6. Adequate kidney function defined as eGFR greater than or equal to 60-70 mL/min/1.73 square meters of body surface area.
 
Dosage and Administration
Dosing per FDA Guidelines unless otherwise specified below.
 
The minimum recommended dose of Exagamlogene autotemcel (e.g., Casgevy) is 3 million CD34+ cells per kg of body weight.
 
Exagamlogene autotemcel (e.g., Casgevy) is available as a single-use intravenous injection.
  
Dosing Limits
One injection per lifetime.
 
Considerations
 
Off-Target genome editing was not observed in the trial, however 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 and will be evaluated in FDA-mandated post marketing studies.
 
Neutrophil engraftment failure is a potential risk, requiring use of unmodified rescue CD34+ cells. It is recommended to monitor absolute neutrophil counts and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, individuals should be infused with rescue CD34+ cells.
 
Longer median platelet engraftment times were observed with exagamglogene autotemcel treatment compared to allogeneic HSC transplant. There is an increased risk of bleeding until platelet engraftment is achieved. It is recommended to monitor for bleeding according to standard guidelines and medical judgment.
 
It is recommended that hydroxyurea, voxelotor, and/or crizanlizumab be discontinued at least 8 weeks prior to the start of mobilization and conditioning as their interaction with exagamglogene autotemcel, mobilization, and myeloablative conditioning are unknown.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Exagamlogene autotemcel (e.g., Casgevy), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Repeat treatment with exagamglogene autotemcel is considered investigational.
 
For members with contracts without primary coverage criteria, Exagamlogene autotemcel (e.g., Casgevy), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 23, 2024 to May 2025
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Exagamlogene autotemcel (e.g., Casgevy) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
SICKLE CELL DISEASE
 
1. Individual is at least 12 years of age (Casgevy, 2023); AND
2. Individual has a documented diagnosis of sickle cell disease confirmed by testing demonstrating the following (Casgevy, 2023):
a. Homozygous sickle cell disease (e.g., HbSS); OR
b. Heterozygous sickle cell disease (e.g., HbSC, HbSBeta+, HbSBeta0, HbSD, HbSOArab, HbSE); AND
3. Individual has a history of recurrent vaso-occlusive crises (VOCs), as evidenced by ≥4 severe VOC(s) in the most recent 24 months (see policy guidelines for a definition of VOC); AND
4. Applicable only to individuals less than 18 years of age: Individual does not have an available and willing matched HLA-identical sibling or haploidentical related hematopoietic cell donor (Frangoul, 2023) (Kassim 2024); AND
5. Individual has not received allogenic hematopoietic stem cell transplant (Casgevy, 2023); AND
6. Individual meets the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see policy guidelines):
a. Adequate Karnofsky performance status or Lansky performance status
b. Absence of advanced liver disease
c. Adequate estimated glomerular filtration rate (eGFR)
d. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO)
e. Adequate left ventricular ejection fraction (LVEF)
f. Absence of clinically significant active infection(s)
7. Individual does not have a history of receiving gene therapy or is not under consideration for treatment with another gene therapy for sickle cell disease; AND
8. Must be dosed in accordance with the FDA label.
 
BETA THALASSEMIA
 
1. Individual is at least 12 years of age (Casgevy, 2023); AND
2. Individual has a documented diagnosis of Beta-thalassemia as evidenced by one of the following genotypes by globin gene testing (Casgevy, 2023):
a. Beta0/Beta0; OR
b. Beta0/Beta0 – like (see policy guidelines); OR
c. Non-Beta0/Beta0 (see policy guidelines); AND
3. Individual requires regular peripheral blood transfusions to maintain target hemoglobin levels as defined by documentation of the following:
a. History of receiving transfusions of ≥100 ml per kilogram of body weight of packed red blood cells per year; OR
b. History of receiving > 8 transfusions per year in the prior 2 years at the time of treatment decision (Frangoul, 2023; Locatelli, 2022); AND
4. Applicable only to individuals less than 18 years of age: Individual does not have an available and willing matched HLA-identical sibling or haploidentical related hematopoietic cell donor (Frangoul, 2023) (Kassim 2024); AND
5. Individual has not received allogenic hematopoietic stem cell transplant (Casgevy, 2023); AND
6. Individual meets the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see policy guidelines):
a. Adequate Karnofsky performance status or Lansky performance status
b. Absence of advanced liver disease
c. Adequate estimated glomerular filtration rate (eGFR)
d. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO)
e. Adequate left ventricular ejection fraction (LVEF)
f. Absence of clinically significant active infection(s)
7. Individual does not have a history of receiving gene therapy or is not under consideration for treatment with another gene therapy for beta thalassemia; AND
8. Must be dosed in accordance with the FDA label.
 
Policy guidelines
 
VOC is defined as either:
 
1. Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or IV NSAIDs) or RBC transfusions; OR
2. Acute chest syndrome; OR
3. Priapism lasting >2 hours and requiring a visit to a medical facility; OR
4. Acute hepatic sequestration; OR
5. Acute splenic sequestration (Frangoul 2023, Kanter 2022, Lowe 2023).
 
Examples of beta thalassemia genotypes
 
1. Beta0/Beta0 – like:
a. Beta0/Beta+ (IVS-I-110)
b. Beta+ (IVS-I-110)/Beta+ (IVS-I-110)
2. Non-Beta0/Beta0:
a. Beta0/Beta+
b. BetaE/Beta0
c. Beta+/Beta+   
 
Institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy may include:
 
1. Adequate cell counts defined as WBC > 3 × 1 billion/L, ANC > 1 x 1 billion/L (> 0.5 x1 billion/L for those on hydroxyurea treatment) or platelets > 50 to 100 × 1 billion/L
2. Adequate heart function defined as LVEF > 45% or cardiac T2* > 10 ms
3. Absence of advanced liver disease (defined as ALT > 3x ULN, AST > 3x ULN, direct bilirubin value > 2x ULN, PT INR > 1.5x ULN, history of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy)
4. Adequate lung function defined as DLCO > 50% of predicted value and baseline oxygen saturation > 90% without supplemental oxygen
5. Adequate performance status defined as Karnofsky performance status > 60 (≥ 16 years of age) or Lansky performance status > 60 (< 16 years of age)
6. Adequate kidney function defined as eGFR > 60 to 70 mL/min/1.73 square meters of body surface area.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The minimum recommended dose of Exagamlogene autotemcel (e.g., Casgevy) is 3 × 1 million CD34+ cells per kg of body weight.
 
Exagamlogene autotemcel (e.g., Casgevy) is available as a single-use intravenous injection.
  
Dosing Limits
One injection per lifetime.
 
Considerations
 
Off-Target genome editing was not observed in the trial, however 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 and will be evaluated in FDA-mandated post marketing studies.
 
Neutrophil engraftment failure is a potential risk, requiring use of unmodified rescue CD34+ cells. It is recommended to monitor absolute neutrophil counts and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, individuals should be infused with rescue CD34+ cells.
 
Longer median platelet engraftment times were observed with exagamglogene autotemcel treatment compared to allogeneic HSC transplant. There is an increased risk of bleeding until platelet engraftment is achieved. It is recommended to monitor for bleeding according to standard guidelines and medical judgment.
 
It is recommended that hydroxyurea, voxelotor, and/or crizanlizumab be discontinued at least 8 weeks prior to the start of mobilization and conditioning as their interaction with exagamglogene autotemcel, mobilization, and myeloablative conditioning are unknown.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Exagamlogene autotemcel (e.g., Casgevy), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
Repeat treatment with exagamglogene autotemcel is considered investigational.
 
For members with contracts without primary coverage criteria, Exagamlogene autotemcel (e.g., Casgevy), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective May 29, 2024 to October 22, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Exagamlogene autotemcel (e.g., Casgevy) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
SICKLE CELL DISEASE
 
1. Individual is at least 12 years of age (Casgevy, 2023); AND  
2. Individual has a documented diagnosis of sickle cell disease confirmed by testing demonstrating the following (Casgevy, 2023):
a. Homozygous sickle cell disease (e.g., HbSS); OR
b. Heterozygous sickle cell disease (e.g., HbSC, HbSBeta+, HbSBeta0, HbSD, HbSOArab, HbSE); AND
3. Individual has a history of recurrent vaso-occlusive crises (VOCs), as evidenced by ≥ 4 severe VOC(s) in the most recent 24 months (see policy guidelines for a definition of VOC); AND  
4. Applicable only to individuals less than 18 years of age: Individual does not have an available and willing matched HLA-identical sibling hematopoietic cell donor (Frangoul, 2023); AND
5. Individual has not received allogenic hematopoietic stem cell transplant (Casgevy, 2023); AND
6. Individual meets the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see policy guidelines).
a. Adequate Karnofsky performance status or Lansky performance status
b. Absence of advanced liver disease
c. Adequate estimated glomerular filtration rate (eGFR)
d. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO)
e. Adequate left ventricular ejection fraction (LVEF)
f. Absence of clinically significant active infection(s).
7. Individual does not have a history of receiving gene therapy or is not under consideration for treatment with another gene therapy for sickle cell disease; AND
8. Must be dosed in accordance with the FDA label.
 
BETA THALASSEMIA
 
1. Individual is at least 12 years of age (Casgevy, 2023); AND  
2. Individual has a documented diagnosis of Beta-thalassemia by globin gene testing (Casgevy, 2023); AND
3. Individual requires regular peripheral blood transfusions to maintain target hemoglobin levels as defined by documentation of the following:
a. History of receiving transfusions of ≥100 ml per kilogram of body weight of packed red blood cells per year; OR
b. History of receiving > 8 transfusions per year in the prior 2 years at the time of treatment decision (Frangoul, 2023; Locatelli, 2022); AND
4. Applicable only to individuals less than 18 years of age: Individual does not have an available and willing matched HLA-identical sibling hematopoietic cell donor (Frangoul, 2023); AND
5. Individual has not received allogenic hematopoietic stem cell transplant (Casgevy, 2023); AND
6. Individual meets the institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy (see policy guidelines).
a. Adequate Karnofsky performance status or Lansky performance status
b. Absence of advanced liver disease
c. Adequate estimated glomerular filtration rate (eGFR)
d. Adequate diffusing capacity of the lungs for carbon monoxide (DLCO)
e. Adequate left ventricular ejection fraction (LVEF)
f. Absence of clinically significant active infection(s).
7. Individual does not have a history of receiving gene therapy or is not under consideration for treatment with another gene therapy for beta thalassemia; AND
8. Must be dosed in accordance with the FDA label.
 
Policy guidelines
 
VOC is defined as either:
1. Acute pain event requiring a visit to a medical facility and administration of pain medications (opioids or IV NSAIDs) or RBC transfusions; OR
2. Acute chest syndrome; OR
3. Priapism lasting >2 hours and requiring a visit to a medical facility; OR
4. Acute hepatic sequestration; OR
5. Acute splenic sequestration (Frangoul 2023, Kanter 2022, Lowe 2023).
 
Institutional requirements for a stem cell transplant procedure where the individual is expected to receive gene therapy may include:
1. Adequate cell counts defined as WBC > 3 × 10 to the ninth power/L, ANC > 1 x 10 to the ninth power/L (> 0.5 x10 to the ninth power/L for those on hydroxyurea treatment) or platelets > 50 to 100 × 10 to the ninth power/L
2. Adequate heart function defined as LVEF > 45% or cardiac T2* > 10 ms
3. Absence of advanced liver disease (defined as ALT > 3x ULN, AST > 3x ULN, direct bilirubin value > 2x ULN, PT INR > 1.5x ULN, history of cirrhosis or any evidence of bridging fibrosis, or active hepatitis on liver biopsy)
4. Adequate lung function defined as DLCO > 50% of predicted value and baseline oxygen saturation > 90% without supplemental oxygen
5. Adequate performance status defined as Karnofsky performance status > 60 (≥ 16 years of age) or Lansky performance status > 60 (< 16 years of age)
6. Adequate kidney function defined as eGFR > 60 to 70 mL/min/1.73 square meters of body surface area.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The minimum recommended dose of exagamlogene autotemcel (e.g., Casgevy) is 3 × 106 CD34+ cells per kg of body weight.
 
Exagamlogene autotemcel (e.g., Casgevy) is available as a single-use intravenous injection.
  
Dosing Limits
One injection per lifetime.
 
Considerations
 
Off-Target genome editing was not observed in the trial, however 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 and will be evaluated in FDA-mandated post marketing studies.
 
Neutrophil engraftment failure is a potential risk, requiring use of unmodified rescue CD34+ cells. It is recommended to monitor absolute neutrophil counts and manage infections according to standard guidelines and medical judgement. In the event of neutrophil engraftment failure, individuals should be infused with rescue CD34+ cells.
 
Longer median platelet engraftment times were observed with exagamglogene autotemcel treatment compared to allogeneic HSC transplant. There is an increased risk of bleeding until platelet engraftment is achieved. It is recommended to monitor for bleeding according to standard guidelines and medical judgment.
 
It is recommended that hydroxyurea, voxelotor, and/or crizanlizumab be discontinued at least 8 weeks prior to the start of mobilization and conditioning as their interaction with exagamglogene autotemcel, mobilization, and myeloablative conditioning are unknown.
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Exagamlogene autotemcel (e.g., Casgevy), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
Repeat treatment with exagamglogene autotemcel is considered investigational.
 
For members with contracts without primary coverage criteria, exagamlogene autotemcel (e.g., Casgevy), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of exagamglogene autotemcel in patients with SCD was evaluated in an open-label, single-arm trial and a long-term follow-up trial, in which 44 adolescent and adult patients with SCD were treated with exagamglogene autotemcel after undergoing myeloablative conditioning with busulfan. The adverse event profile was consistent with that expected from busulfan myeloablative conditioning and HSC transplant. The median (min, max) duration of follow-up for 44 patients with SCD after being administered exagamglogene autotemcel was 19.3 (0.8, 48.1) months. Serious adverse reactions after myeloablative conditioning and exagamglogene autotemcel infusion were observed in 45% of patients with SCD. The most common serious adverse reactions (≥ 2 patients) were cholelithiasis, pneumonia, abdominal pain, constipation, pyrexia, abdominal pain upper, non-cardiac chest pain, oropharyngeal pain, pain, and sepsis. One (2%) patient died due to a COVID-19 infection and subsequent respiratory failure. The event was not related to exagamglogene autotemcel.
 
Evaluation of exagamglogene autotemcel for beta thalassemia was supported by results from the CLIMB THAL-111 trial (NCT03655678), an ongoing open-label, multicenter, single-arm trial to evaluate the safety and efficacy of Casgevy in adult and adolescent patients with TDT. The transfusion independence (TI) for 12 consecutive months (TI12) responder rate was 32/35 (91.4%, 98.3% one-sided CI: 75.7%, 100%). All patients who achieved TI12 remained transfusion independent, with a median (min, max) duration of TI of 20.8 months (13.3, 45.1) and normal mean weighted average total hemoglobin levels (mean standard deviation [SD] 13.1 [1.4] g/dL).
 
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2025. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
38241Hematopoietic progenitor cell (HPC); autologous transplantation
96365Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96374Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug
96376Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); each additional sequential intravenous push of the same substance/drug provided in a facility (List separately in addition to code for primary procedure)
96409Chemotherapy administration; intravenous, push technique, single or initial substance/drug
96413Chemotherapy administration, intravenous infusion technique; up to 1 hour, single or initial substance/drug
C9399Unclassified drugs or biologicals
J3392Injection, exagamglogene autotemcel, per treatment
J3590Unclassified biologics
References: Brusson M, et al.(2021) Genome editing approaches to B-hemoglobinopathies Prog Mol Biol Transl Sci. 2021;182:153-183. doi:10.1016/bs.pmbts.2021.01.025

Casgevy [package insert]. Boston, MA: Vertex Pharmaceuticals inc.; 2024.

Casgevy(2023) package insert Boston, MA: Vertex Pharmaceuticals; 2023.

Frangoul H, et al.(2021) CRISPR-Cas9 gene editing for sickle cell disease and beta-thalassemia. N Engl J Med. 2021;384(3):252-260. doi:10.1056/NEJMoa2031054

Frangoul H, et al.(2023) Exagamglogene autotemcel for severe sickle cell disease. Abstract presented at: 65th American Society of Hematology Annual Meeting; December 11, 2023; San Diego, CA. Accessed January 11, 2024. https://ash.confex.com/ash/2023/webprogram/Paper190139.html

Frangoul H, Locatelli F, Sharma A, Bhatia M, Mapara M, Molinari L, Wall D, Liem RI, Telfer P, Shah AJ, Cavazzana M.(2023) Exagamglogene Autotemcel for Severe Sickle Cell Disease. Blood. 2023 Nov 28;142:1052.

Fujikura K, Cheng AL, Suriany S, Detterich J, Arai AE, Wood JC.(2022) Myocardial iron overload causes subclinical myocardial dysfunction in sickle cell disease Cardiovascular Imaging. 2022 Aug 1;15(8):1510-2.

Kanter J, Walters MC, Krishnamurti L, et al.(2022) Biologic and clinical efficacy of Lovotibeglogene autotemcel for sickle cell disease. N Engl J Med 2022;386:617-28. DOI: 10.1056/NEJMoa2117175

Kassim AA, et al.(2024) An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease. Blood. 2024 Jun 20;143(25):2654-2665. doi: 10.1182/blood.2023023301. PMID: 38493482.

Locatelli, F, et al(2022) Betibeglogene Autotemcel Gene Therapy for Non-B0/B0 Genotype B-Thalassemia. N Engl J Med. 2022 Feb 3;386(5):415-427. doi: 10.1056/NEJMoa2113206. Epub 2021 Dec 11. PMID: 34891223

Lowe M, Bambhroliya Z, Patel H, Patel VJ, Vudugula SA, Cheruvu NP, Raza S, Okunlola OI, Okunlola O.(2023) Emerging Therapies for the Management of Pain and Vaso-Occlusive Crises in Patients With Sickle Cell Disease: A Systematic Review of Randomized Controlled Trials. Cureus. 2023 Apr 23;15(4).

Modarai SR, et al.(2021) Precise and error-prone CRISPR-directed gene editing activity in human CD34+ cells varies widely among patient samples. Gene Ther. 2021;28(1–2):105–113. doi:10.1038/s41434-020-00192-z

Niihara Y, et al.(2018) A Phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226-235. doi:10.1056/NEJMoa1715971

Vertex and CRISPR Therapeutics announce US FDA approval of Casgevy (exagamglogene autotemcel) for the treatment of sickle cell disease. Press release. Vertex Pharmaceuticals; December 8, 2023. Accessed January 31, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-and-crispr-therapeutics-announce-us-fda-approval

Vertex Pharmaceuticals. Third quarter 2023 financial results [investor presentation]. November 6, 2023. Accessed January 31, 2024. https://investors.vrtx.com/static-files/03c42305-90c3-4fa9-9ef7-a1aca11e40f9
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