Last Review Date: 02/01/2024

Date of Origin: 01/04/2024

Dates Reviewed: 01/2024, 02/2024

1. Length of Authorization

Coverage will be provided for one treatment course (1 dose of Casgevy) and may not be renewed.

2. Dosing Limits

1. Quantity Limit (max daily dose) [NDC Unit]:

• A single dose of Casgevy containing a minimum of 3.0 × 10⁶ CD34+ cells/kg of body weight, in multiple vials

2. Max Units (per dose and over time) [HCPS Unit]:

• A single dose of Casgevy containing a minimum of 3.0 × 10⁶ CD34+ cells/kg of body weight, in multiple vials

3. Initial Approval Criteria ¹

Coverage is provided in the following conditions:

• Patient is at least 12 years of age; AND
• Provider has considered use of prophylaxis therapy for seizures prior to initiating myeloablative conditioning; AND
• Patient has been screened and found negative for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus 1 &2 (HIV-1/HIV-2) in accordance with clinical guidelines prior to collection of cells (leukapheresis); AND
• Must not be administered concurrently with live vaccines while immunosuppressed; AND
• Patient does not have a history of hypersensitivity to dimethyl sulfoxide (DMSO) or dextran 40; AND
• Patient has not received other gene therapies [e.g., Lyfgenia®(lovotibeglogene autotemcel), Zynteglo® (betibeglogene autotemcel), etc.]**; AND
• Patient will not receive therapy concomitantly with any of the following:
  • Iron chelators for 7-days prior to mobilization and 6 months post-treatment (3-months post-treatment for non-myelosuppressive iron chelators); AND
  • Disease-modifying agents (e.g., hydroxyurea, voxelotor, or crizanlizumab) for at least 8-weeks prior to mobilization and conditioning; AND
• Patient is a candidate for autologous hematopoietic stem cell transplant (HSCT) and has not had prior HSCT; AND
• For patients under 18 years of age, the patient does not have a known and suitable 10/10 human leukocyte antigen matched related donor willing to participate in an allogeneic HSCT; AND

Sickle Cell Disease † Ф

• Patient has a confirmed diagnosis of sickle-cell disease with one of the following genotypes βS/βS or βS/β0 or βS/β+ (Note: Additional genotypes will be considered on a case-by-case basis based on disease severity) as determined by one of the following:
  • Identification of significant quantities of HbS with or without an additional abnormal β-globin chain variant by hemoglobin assay; OR
  • Identification of biallelic HBB pathogenic variants where at least one allele is the p.Glu6Val pathogenic variant on molecular genetic testing; AND
• Patient has symptomatic disease despite treatment with hydroxyurea at any point in the past OR add-on therapy (e.g., crizanlizumab, voxelotor, etc.) OR has experienced intolerance; AND
• Patient experienced two or more vaso-occlusive event/crises (VOE/VOC)* in the previous year; AND

• Patient will be transfused prior to apheresis to a total Hb ≤ 11 g/dL and a HbS level <30% and patient will be transfused at least 8 weeks prior to initiation of myeloablative conditioning (with aforementioned Hb and HbS goals); AND
• Patient will not receive granulocyte-colony stimulating factor (G-CSF) for the mobilization of hematopoietic stem cells (HSC)

 *VOE/VOC is defined as an event requiring a visit to a medical facility for evaluation which results in a diagnosis of such being documented due to one (or more) of the following: acute pain, acute chest syndrome, acute splenic sequestration, acute hepatic sequestration, priapism lasting > 2 hours AND necessitating subsequent interventions such as opioid pain management, non-steroidal anti-inflammatory drugs, RBC transfusion, etc.

Beta Thalassemia † ^1,10,12

• Patient has a documented diagnosis of homozygous beta thalassemia or compound heterozygous beta thalassemia including β-thalassemia/hemoglobin E (HbE) as outlined by the following:
  • Patient diagnosis is confirmed by HBB sequence gene analysis showing biallelic pathogenic variants; OR
  • Patient has severe microcytic hypochromic anemia, absence of iron deficiency, anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and hemoglobin analysis that reveals decreased amounts or complete absence of hemoglobin A (HbA) and increased HbA₂ with or without increased amounts of hemoglobin F (HbF); AND
• Patient has transfusion-dependent disease defined as a history of transfusions of at least 100 mL/kg/year or ≥10 units/year of packed red blood cells (pRBCs) in the 2 years preceding therapy; AND
• Patient will be transfused prior to apheresis to a total Hb ≥ 11 g/dL for 60 days prior to myeloablative conditioning; AND
• Patient does not have any of the following:
  • Severely elevated iron in the heart (i.e., patients with cardiac T2* less than 10 msec by magnetic resonance imaging [MRI] or left ventricular ejection fraction [LVEF] < 45% by echocardiogram); OR
  • Advanced liver disease [i.e., AST or ALT > 3 times the upper limit of normal (ULN), or direct bilirubin value > 2.5 times the ULN, or if a liver biopsy demonstrated bridging fibrosis or cirrhosis]

** Requests for subsequent use of exagamglogene after receipt of other gene therapies (e.g., lovotibeglogene, betibeglogene, etc.) will be evaluated on a case-by-case basis

† FDA Approved Indication(s); ‡ Compendia Recommended Indication(s); Ф Orphan Drug

4. Renewal Criteria ^1,3

• Coverage cannot be renewed.

5. Dosage/Administration ¹

6. Billing Code/Availability Information

HCPCS:

• J3590 – Unclassified biologics
• C9399 – Unclassified drugs or biologicals (for hospital outpatient use ONLY)

NDC:

• Casgevy containing a minimum of 3.0 × 10⁶ CD34+ cells/kg of body weight, in multiple vials supplied in vial(s) packaged in carton(s): 51167-0290-xx

7. References

1. Casgevy [package insert]. Boston, MA; Vertex, Inc., January 2024. Accessed January 2024.
2. Frangoul H, Altshuler D, Cappellini D, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. Jan 21, 2021 N Engl J Med 2021; 384:252-260 DOI: 10.1056/NEJMoa2031054.
3. Bender MA, Carlberg K. Sickle Cell Disease. 2003 Sep 15 [Updated 2022 Nov 17]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1377/.
4. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48.
5. Tisdale JF, Pierciey FJ, Bonner M, et al. (2020) Safety and feasibility of hematopoietic progenitor stem cell collection by mobilization with plerixafor followed by apheresis vs bone marrow harvest in patients with sickle cell disease in the multi-center HGB-206 trial. Am J Hematol E239–E242. https://doi.org/10.1002/ajh.25867.
6. Palmer J, McCune JS, Perales M-A, et al. (2016) Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biol Blood Marrow Transplant 1915–1925. https://doi.org/10.1016/j.bbmt.2016.07.013
7. Brunson A, Keegan THM, Bang H, et al. (2017) Increased risk of leukemia among sickle cell disease patients in California. Blood 130:1597–1599. doi: 10.1182/blood-2017-05-783233.
8. Seminog OO, Ogunlaja OI, Yeates D, Goldacre MJ (2016) Risk of individual malignant neoplasms in patients with sickle cell disease: English national record linkage study. J R Soc Med 109:303–309. doi: 10.1177/0141076816651037.
9. Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.
10. Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054. Epub 2020 Dec 5.
11. Modarai SR, Kanda S, Bloh K, et al. Precise and error-prone CRISPR-directed gene editing activity in human CD34+ cells varies widely among patient samples. Gene Ther. 2021 Feb;28(1-2):105-113. doi: 10.1038/s41434-020-00192-z. Epub 2020 Sep 1.
12. Origa R. Beta-Thalassemia. 2000 Sep 28 [Updated 2023 July 20]. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1426/. Accessed January 2024.
13. Locatelli F, Thompson AA, Kwiatkowski JL, et al. Betibeglogene Autotemcel Gene Therapy for Non-β(0)/β(0) Genotype β-Thalassemia. N Engl J Med. 2022 Feb 3;386(5):415-427. doi: 10.1056/NEJMoa2113206. Epub 2021 Dec 11.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

The preceding information is intended for non-Medicare coverage determinations. Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.

Medicare Part B Covered Diagnosis Codes (applicable to existing NCD/LCA/LCD): N/A