BCBS MA gene therapy coverage & Prior Auth

Coverage Criteria for Betibeglogene and Exagamglogene Autotemcel

Initial therapy — Betibeglogene autotemcel

Betibeglogene autotemcel (Zynteglo) is considered medically necessary when ALL of the following are met:

Zynteglo initial eligibility: 1. Documented diagnosis of β-thalassemia by globin gene testing; AND 2. Requires regular peripheral blood transfusions to maintain target hemoglobin levels; AND 3. Documented history of receiving transfusions of ≥100 mL/kg/year of packed red blood cells or ≥8 transfusions per year in the previous 2 years at the time of treatment decision; AND 4. Karnofsky performance status ≥80 for adults (≥16 years) or Lansky performance status ≥80 for adolescents (<16 years); AND 5. Negative serologic test for HIV infection; AND 6. Individual does not have any of the following exclusions: i. A provider-determined unacceptable risk–benefit when an HLA-identical or matched donor is willing and available; OR ii. T2*-weighted MRI myocardial iron <10 msec or other evidence of severe iron overload in the treating physician's opinion; OR iii. Advanced liver disease as evidenced by any of: a) persistent AST, ALT, or direct bilirubin >3× ULN; OR b) baseline PT or PTT >1.5× ULN; OR c) MRI demonstrating clear evidence of cirrhosis; OR d) liver biopsy showing cirrhosis, bridging fibrosis, or active hepatitis; OR iv. Baseline estimated glomerular filtration rate <70 mL/min/1.73 m2; OR v. History of prior gene therapy or prior allogeneic hematopoietic stem cell transplant; OR vi. Any prior or current malignancy (except adequately treated in situ cervical carcinoma and basal/squamous cell skin carcinoma) or myeloproliferative/significant immunodeficiency disorder; OR vii. Immediate family history (parent or sibling) of a known familial cancer syndrome; OR viii. Active, uncontrolled hepatitis C or hepatitis B infection; OR ix. Contraindication to required agents for myeloablative conditioning (e.g., G-CSF, plerixafor, busulfan) including hypersensitivity; OR x. White blood cell count <3 × 10^9/L and/or platelet count <100 × 10^9/L not related to hypersplenism.

See policy exclusions for full details.

Initial therapy — Exagamglogene autotemcel

Exagamglogene autotemcel (Casgevy) is considered medically necessary when ALL of the following are met:

Casgevy initial eligibility: 1. Documented diagnosis of β-thalassemia by globin gene testing (e.g., β-thalassemia major or thalassemia intermedia); AND 2. Requires regular peripheral blood transfusions as defined by either: i) history of ≥100 mL/kg/year of packed red blood cells OR ii) history of ≥8 transfusions per year in the previous 2 years at the time of treatment decision; AND 3. Meets institutional requirements for a stem cell transplant procedure (adequate performance status [Karnofsky or Lansky], absence of advanced liver disease, adequate eGFR, adequate left ventricular ejection fraction, and absence of clinically significant active infection); AND 4. Does not have T2*-weighted MRI myocardial iron <10 msec or other evidence of severe iron overload per treating physician; AND 5. Has not received a prior allogeneic hematopoietic stem cell transplant; AND 6. Does not have a current application pending for another gene therapy for beta thalassemia.

Repeat treatment with exagamglogene autotemcel is considered investigational.

Investigational / Not covered indications

Investigational conditions: Betibeglogene autotemcel or exagamglogene autotemcel is considered investigational when the above applicable medical necessity criteria are not met; repeat treatment with either product is investigational (not medically necessary); both products are investigational for all other indications (exagamglogene autotemcel exception: sickle cell disease addressed separately in policy #050).

Coverage for betibeglogene autotemcel and exagamglogene autotemcel

Covered when ALL of the following are met (as supported by clinical trials and labeling):

Primary coverage criteria: 1. Patient has transfusion-dependent β-thalassemia as defined in clinical studies (history of ≥100 mL/kg/year of packed red blood cells or ≥8 transfusions per year in the prior 2 years); AND 2. Patient meets genotype or study enrollment criteria per product labeling (e.g., non-β0/β0 genotypes included in betibeglogene programs; homozygous or compound heterozygous including HbE/beta-thalassemia included in exagamglogene programs); AND 3. A single-dose intravenous infusion of the indicated gene therapy will be administered following myeloablative conditioning consistent with trial protocols and product labeling (one-time administration).

Efficacy observed: transfusion independence achieved in ~89% (betibeglogene, 36 evaluable) and ~91% (exagamglogene, 35 evaluable interim). Long-term follow-up (>15 years) is required to establish durability.

Specific exclusion conditions for betibeglogene autotemcel include severe myocardial iron overload (for example, a T2*-weighted MRI myocardial iron measurement of 10 msec) and evidence of advanced liver disease. Advanced liver disease is defined by any of the following: persistent AST, ALT, or direct bilirubin > 3× the upper limit of normal; baseline PT or PTT > 1.5× the upper limit of normal; MRI evidence of cirrhosis; or liver biopsy demonstrating cirrhosis, bridging fibrosis, or active hepatitis. Additional exclusions include baseline estimated glomerular filtration rate < 70 mL/min/1.73 m2, history of prior gene therapy or allogeneic hematopoietic stem cell transplant, prior or current malignancy (with limited exceptions), an immediate family history of a known familial cancer syndrome, active uncontrolled hepatitis B or C infection, contraindication to required conditioning agents (eg, G-CSF, plerixafor, busulfan), and a white blood cell count < 3 × 10^9/L and/or platelet count < 100 × 10^9/L not related to hypersplenism.

The evidence base for both betibeglogene and exagamglogene autotemcel is limited by small sample sizes and relatively short follow-up in the available trials. Published studies are single-arm and open-label, creating uncertainty around estimates of both benefit and rare harms; for betibeglogene the pooled phase III analysis included 41 dosed individuals with 36 evaluable for the primary efficacy analysis, and for exagamglogene the interim analysis included 35 evaluable participants. Long-term durability of response and the frequency of rare but serious adverse events (for example, insertional oncogenesis or late treatment-related malignancy) remain uncertain and require planned long-term follow-up of > 15 years to better define risks and durability. Additionally, standard treatment alternatives (transfusion and iron chelation, and allogeneic HSCT when available) and their complications factor into clinical decision-making.

Repeat administration of either betibeglogene autotemcel (Zynteglo) or exagamglogene autotemcel (Casgevy) is explicitly considered investigational / not medically necessary in this policy. Both products are studied and authorized as single-dose autologous gene therapies; prior trials and the policy language indicate repeat treatment is not supported by current evidence.

This policy does not provide a comprehensive list of every possible scenario that would be deemed not medically necessary. Rather, it states that the products are investigational when the specified eligibility criteria are not met and highlights evidence limitations (for example, small sample sizes and limited duration of follow-up) that inform the investigational determinations.

Regimens, Dosing, and Monitoring Requirements

Monitoring / Safety topic	Recommendation / Timing
Iron chelator interactions with myeloablative conditioning
Consider drug–drug interactions with conditioning agents; discontinue iron chelators at least 7 days prior to initiation of conditioning

Monitoring / Safety topic	Recommendation / Timing
Post-infusion avoidance period for iron chelators
Avoid non‑myelosuppressive iron chelators for ≥3 months and avoid myelosuppressive iron chelators for ≥6 months after infusion; phlebotomy may be used when appropriate
Age limit noted in FDA labeling
Products not studied in patients >65 years of age per FDA label
Lentiviral insertional oncogenesis monitoring (betibeglogene autotemcel only)
Monitor for hematologic malignancies at month 6, month 12, then annually for at least 15 years after treatment
Administration regimen
One‑time intravenous infusion following myeloablative conditioning (single‑dose autologous lentiviral gene therapy per trials and labels)

Coding and Dose Thresholds

HCPCS CodesHCPCS

C9399	Unclassified drugs or biologicals.
J3392	Injection, exagamglogene autotemcel, per treatment (Casgevy®).
J3393	Injection, betibeglogene autotemcel, per treatment (Zynteglo®).
J3490	Unclassified drugs.
J3590	Unclassified biologics

ICD-10 Procedure CodesICD-10

XW133B8	Transfusion of Betibeglogene Autotemcel into Peripheral Vein, Percutaneous Approach, New Technology Group 8.
XW133J8	Transfusion of Exagamglogene Autotemcel into Peripheral Vein, Percutaneous Approach, New Technology Group 8.
XW143B8	Transfusion of Betibeglogene Autotemcel into Central Vein, Percutaneous Approach, New Technology Group 8.
XW143J8	Transfusion of Exagamglogene Autotemcel into Central Vein, Percutaneous Approach, New Technology Group 8.

Referenced gene therapy products / prescribing labelsmixed

Zynteglo	Betibeglogene autotemcel — product name referenced in prescribing label
Casgevy	Exagamglogene autotemcel — product name referenced in prescribing label

Minimum CD34+ cell dose — Betibeglogene and Exagamglogene minimum doses

Betibeglogene autotemcel (minimum CD34+ dose)5.0 × 10^6 CD34+ cells/kg of body weight.

Exagamglogene autotemcel (minimum CD34+ dose)3.0 × 10^6 CD34+ cells/kg of body weight.

Dosing lifetime limit (Exagamglogene)1 injection per lifetime (per product dosing limits).

Transfusion dependence definition used in studies — ≥100 mL/kg/year or ≥8 transfusions/year (prior 2 years)

Study definition — volume-basedHistory of at least 100 mL/kg/year of peripheral red blood cells for the prior 2 years.

Study definition — transfusion count

Prior Authorization, Documentation, and Operational Requirements

Prior Authorization

Prior Authorization Required

Prior authorization required for listed gene therapy products and for inpatient services. Precertification/preauthorization is REQUIRED for all services performed inpatient. For outpatient settings, prior authorization is required for Commercial HMO/POS, Commercial PPO/Indemnity, Medicare HMO, and Medicare PPO. Use Authorization Manager to submit requests and supporting documentation.

Inpatient services: precertification/preauthorization is REQUIRED.
Outpatient services: prior authorization is REQUIRED for Commercial Managed Care (HMO and POS), Commercial PPO and Indemnity, Medicare HMO Blue SM, Medicare PPO Blue SM.

Prior Authorization

Prior Authorization for Gene Therapy Products

Prior authorization is required specifically for the gene therapies listed below. Complete and fax the appropriate Prior Authorization Request Form (forms must be completed and faxed to the numbers below). Providers should submit initial authorization requests via Authorization Manager and include all required supporting clinical documentation.

Zynteglo™ (Betibeglogene autotemcel) for Beta thalassemia — Prior Authorization Request Form #216.

Genotype and Biomarker Requirements

HBB genotype requirements (eg non-β0/β0 vs β0/β0, IVS1-110 variant, compound heterozygous including HbE) — genotype details for eligibility

Genotype required for betibeglogene eligibilityNon–β0/β0 genotypes (eg, genotypes other than β0/β0) were included in betibeglogene trial programs and align with product labeling enrollment criteria.

β0/β0 genotypeβ0/β0 denotes no beta globin production (associated with more severe phenotype); may not meet betibeglogene trial inclusion that focused on non‑β0/β0 genotypes.

IVS1‑110 and other variantsSpecific HBB variants (eg, IVS1‑110) and compound heterozygous genotypes including HbE/beta‑thalassemia are recognized genotype categories relevant to eligibility and trial enrollment (particularly for exagamglogene).

Key Definitions

Transfusion-dependent β-thalassemia — definition used in policy (≥100 mL/kg/year or ≥8 transfusions/year)

Policy definition — transfusion dependenceHistory of at least 100 mL/kg/year of peripheral red blood cells or ≥8 transfusions per year for the prior 2 years.

Clinical significanceUsed to identify patients with transfusion‑dependent β‑thalassemia for eligibility for gene therapy programs.

Source of definitionDefinition as applied in clinical trials reviewed and in the policy evidence summary.

Transfusion independence — weighted average Hb ≥9 g/dL without transfusions for continuous 12 months after infusion

Transfusion independence — numeric thresholdWeighted average hemoglobin ≥9 g/dL without any transfusions for a continuous 12‑month period after infusion.

Clinical trial application

Background on β-Thalassemia and Gene Therapy

β‑thalassemia is an inherited disorder of the HBB gene that reduces or abolishes production of the β‑globin chain of hemoglobin, resulting in ineffective erythropoiesis and chronic anemia. Patients with transfusion‑dependent disease require regular red blood cell transfusions and are at risk for iron overload and associated organ damage, impaired quality of life, and reduced life expectancy compared with unaffected individuals. Transfusion dependence in clinical studies is defined as a history of at least 100 mL/kg/year of packed red blood cells or ≥ 8 transfusions per year for the prior 2 years, and transfusion independence after therapy is commonly defined as a weighted average hemoglobin ≥ 9 g/dL without transfusions for a continuous period of at least 12 months.

OpenPayer

Gene therapy for transfusion-dependent β-thalassemia (betibeglogene and exagamglogene autotemcel)