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Lovotibeglogene autotemcel (Lyfgenia®)
08.02.15

Policy

MEDICALLY NECESSARY


Lyfgenia® (lovotibeglogene autotemcel) is considered medically necessary and, therefore, covered for the treatment of severe sickle cell disease (SCD) in individuals with age ≥ 12 years ​when ALL of the associated criteria for them are met:​

 

  • Individual has diagnosis of severe SCD with one of the following genotypes as confirmed by genetic testing results [(a or b):

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 had been treated with at least ONE pharmacologic treatment for sickle cell disease (e.g., pharmacologic treatment for sickle cell disease include hydroxyurea, Lglutamine, Adakveo (crizanlizumab-tmca intravenous infusion), and Oxbryta (voxelotor tablets and tablets for oral suspension));
  • ​While receiving appropriate standard treatment for sickle cell disease, individual had at least four severe vaso-occlusive crises or events (VOCs/VOEs) in the previous two 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 which 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 (acute hepatic sequestration is 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 (acute splenic sequestration is 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 sickle cell disease.

EXPERIMENTAL/INVESTIGATIONAL

 

All other uses, including when the above criteria are not met, for Lyfgenia® (lovotibeglogene autotemcel)​ 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

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, lovotibeglogene autotemcel (Lyfgenia) 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, the FDA approved lovotibeglogene autotemcel (Lyfgenia) for the treatment of SCD in individuals ages 12 and older who have a history of vaso-occlusive events (VOEs). Lovotibeglogene autotemcel (Lyfgenia) is a one-time gene therapy that offers the potential to resolve VOEs and is custom-designed to treat the underlying cause of SCD. Lovotibeglogene autotemcel (Lyfgenia) will be available at bluebirdbio's established network of Qualified Treatment Centers (QTCs), which receive specialized training to administer complex gene therapies like lovotibeglogene autotemcel (Lyfgenia). 


SICKLE CELL DISEASE

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

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, ii, iii, and iv]:
i. Disease-modifying therapies for sickle cell disease for at least 2 months before the planned start of mobilization and conditioning (e.g., disease-modifying therapies for sickle cell disease 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);
i. Disease-modifying therapies for sickle cell disease for at least 2 months; AND Note: Examples of disease-modifying therapies for sickle cell disease include hydroxyurea, Adakveo, L-glutamine, and Oxbryta. 
iii.  Erythropoietin for at least 2 months;  
iv. Anti-retrovirals (prophylactic for human immunodeficiency virus [HIV]) for at least 1 month (e.g., anti-retrovirals for HIV include abacavir, emtricitabine, lamivudine, and zidovudine.

  • 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 (a 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; a 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-lymphotrophic virus-1 and -2 AND​

DOSING AND FREQUENCY 

The recommended dose of lovotibeglogene autotemcel (Lyfgenia) is a one-time (per lifetime) single intravenous infusion of 3 × 106 CD34+ cells per kg based on current body weight in kg (within the past 30 days).

Description

LOVOTIBEGLOGENE AUTOTEMCEL (LYFGENIA)


Lovotibeglogene autotemcel, also known as lovo-cell, is branded as Lyfgenia (bluebird bio, Inc.). Lovotibeglogene autotemcel (Lyfgenia) is a cell-based gene therapy that contains human blood stem cells that are genetically modified with a replication-incompetent, self-inactivating lentiviral vector (LVV), a gene delivery vehicle. Lovotibeglogene autotemcel (Lyfgenia) works by adding functional copies of a modified β-globin gene into the individual's hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After a one-time, single-dose intravenous Lovotibeglogene autotemcel (Lyfgenia) infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce red blood cells (RBCs) containing biologically active βA-T87Q-globin that will combine with α-globin to produce functional hemoglobin (Hb) containing βA-T87Q-globin (HbAT87Q). HbAT87Q has similar oxygen-binding affinity to hemoglobin A (HbA). Thus, RBCs containing HbAT87Q have a lower risk of sickling and occluding blood flow, thereby, reducing vaso-occlusive events (VOEs).

 

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 lovotibeglogene autotemcel (Lyfgenia) manufacturing. The cells are, then, genetically modified ex vivo (outside the body) with BB305 LVV to introduce the HbAT87Q gene. Prior to the lovotibeglogene autotemcel (Lyfgenia) infusion, the individual will undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the genetically-modified autologous cells in lovotibeglogene autotemcel (Lyfgenia), as part of a hematopoietic (blood) stem cell transplant (HSCT) procedure.

 

Although there are no known contraindications, lovotibeglogene autotemcel (Lyfgenia) carries a boxed warning for hematologic malignancy. At the time of initial product approval, two individuals treated with an earlier version of lovotibeglogene autotemcel (Lyfgenia) using a different manufacturing process and transplant procedure developed acute myeloid leukemia (AML). One individual with α-thalassemia trait was diagnosed with myelodysplastic syndrome (MDS). The additional hematopoietic stress associated with mobilization, conditioning, and infusion of lovotibeglogene autotemcel (Lyfgenia), including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy. Additional labeled warnings and precautions include delayed platelet engraftment, neutrophil engraftment failure (defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after lovotibeglogene autotemcel [Lyfgenia] infusion), potential risk of lentiviral vector-mediated insertional oncogenesis, and hypersensitivity reactions (including anaphylaxis due to the dimethyl sulfoxide (DMSO) or dextran 40 in lovotibeglogene autotemcel [Lyfgenia]).

 

The most common adverse reactions of Grade 3 or more (incidence of 20% or more) were stomatitis, thrombocytopenia, neutropenia, febrile neutropenia, anemia, and leukopenia.

 

Per the label, individuals should not take prophylactic human immunodeficiency virus (HIV) anti-retroviral medications for at least 1 month prior to mobilization and until all cycles of apheresis are completed. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication.

 

Individuals who have received lovotibeglogene autotemcel (Lyfgenia) are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to integrated BB305 LVV proviral DNA, resulting in a possible false-positive PCR assay test result for HIV. Therefore, individuals who have received lovotibeglogene autotemcel (Lyfgenia) should not be screened for HIV infection using a PCR-based assay.

 

Individuals should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed. If hydroxyurea is administered between mobilization and conditioning, discontinue 2 days prior to initiation of conditioning.

 

Individuals are not to receive myelosuppressive iron chelators for 6 months post-treatment with lovotibeglogene autotemcel (Lyfgenia).

 

The safety and efficacy of lovotibeglogene autotemcel (Lyfgenia) in children younger than 12 years of age have not been established. Lovotibeglogene autotemcel (Lyfgenia) has not been studied in individuals 65 years of age and older. In addition, Lovotibeglogene autotemcel (Lyfgenia) has not been studied in individuals with HIV-1 or HIV-2.

 

SICKLE CELL DISEASE 


Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by the presence of hemoglobin S (HbS), which causes 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. Autologous hematopoietic stem cell-based gene therapy has been studied for a potential treatment of SCD.


PEER-REVIEWED LITERATURE 


The safety and effectiveness of lovotibeglogene autotemcel (Lyfgenia) is based on the data from a single-arm, 24-month, open-label, multicenter Phase 1/2 study in individuals (12 to 50 years) with SCD and history of VOEs (defined as episodes of acute pain with no medically determined cause other than a vaso-occlusion, lasting more than two hours and severe enough to require care at a medical facility). Thirty-six individuals received the intravenous infusion of lovotibeglogene autotemcel (Lyfgenia) with a median (min, max) dose of 6.4 (3,14) × 106 CD34+ cells/kg (48 hours after the last myeloablative busulfan conditioning dose). As lovotibeglogene autotemcel (Lyfgenia) is an autologous therapy, prophylactic long-term immunosuppressive agents were not required. No individuals experienced graft failure or graft rejection. Thirty-two individuals were evaluable for the endpoints of complete resolution of VOEs (VOE-CR) and severe VOEs in the 6-18 months post lovotibeglogene autotemcel (Lyfgenia) infusion including eight adolescent individuals. Severe VOEs were resolved in 30 out of 32 individuals (94%), and 28 out of 32 individuals (88%) achieved VOE-CR during this time period.

 

Individuals treated with lovotibeglogene autotemcel (Lyfgenia) in bluebirdbio-sponsored clinical studies will be monitored for a total of 15 years through a long-term safety and efficacy follow-up study.

SUMMARY

For individuals who are 12 years and older with sickle cell disease who receive lovotibeglogene autotemcel, 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 HGB-206 (Group-C) trial, a total of 36 participants received a single intravenous infusion of lovotibeglogene autotemcel. Of the 36 total participants, 32 were evaluable for the endpoints of complete resolution of vaso-occlusive events (VOEs) and severe VOEs (sVOEs) in the 6 to 18 months post-infusion. Severe VOEs were eliminated for 94% (30/32) and all VOEs were eliminated for 88% (28/32) of evaluable study participants between 6- and 18- months post-infusion. Safety data included 54 study participants who initiated stem cell collection. Three cases of hematologic malignancy (2 cases of acute myeloid leukemia and 1 case of myelodysplastic syndrome) were reported in the pivotal trial. As per the prescribing label, individuals treated with lovotibeglogene autotemcel should have lifelong monitoring for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment, and integration site analysis at months 6, 12, and as warranted. Other adverse reactions were related to myeloablative conditioning or underlying disease. 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 period. After the primary evaluation period to last follow-up, four of the 28 trial participants who achieved complete resolution of VOE (VOE-CR) experienced VOEs. After the primary evaluation period up to 24 months, 17 of 35 (49%) trial participants were prescribed opioids for sickle cell and non-sickle cell-related pain. 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 still remains about the degree of risk of insertional oncogenesis with lovotibeglogene autotemcel in real-world practice. While there is residual uncertainty around the estimates of some of the clinical outcomes, the observed magnitude of the benefit indicates that lovotibeglogene autotemcel will frequently be successful in treating sickle cell disease in at least the short-term. 

References

bluebird bio, Inc. bluebird bio announces FDA approval of Misspelled WordLyfgenia ((Misspelled Wordlovotibeglogene Misspelled Wordautotemcel) for patients ages 12 and older with sickle cell disease and a history of Misspelled Wordvaso-occlusive events. Press Release. Somerville, MA: bluebird bio; December 8, 2023a.


bluebird bio, Inc. Misspelled WordLyfgenia (Misspelled Wordlovotibeglogene Misspelled Wordautotemcel) suspension for intravenous infusion. Prescribing Information. Somerville, MA: bluebird bio; revised December 2023b.


Centers for Disease Control and Prevention (CDC), National Center on Birth Defects and Developmental Disabilities. What is sickle cell disease? [internet[. Atlanta, GA: CDC; last reviewed July 6, 2023. Available at: https://www.cdc.gov/ncbddd/sicklecell/facts.html. Accessed January 12, 2024.


Field JJ, Misspelled WordVichinsky EP. Overview of the management and prognosis of sickle cell disease. Misspelled WordUpToDate [online serial]. Waltham, MA: Misspelled WordUpToDate; October 2023.


Khan S, Rodgers GP. Hematopoietic stem cell transplantation in sickle cell disease. Misspelled WordUpToDate [online serial]. Waltham, MA: Misspelled WordUpToDate; reviewed February 2023.


National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). Evidence-based management of sickle cell disease: Expert panel report, 2014. Bethesda, MD: NIH; September 2014. Available at: https://www.nhlbi.nih.gov/health-topics/evidence-based-management-sickle-cell-disease. Accessed December 13, 2023.


Misspelled WordSedrak A, Misspelled WordKondamudi NP. Sickle cell disease. In Misspelled WordStatPearls [Internet]. Treasure Island, FL: Misspelled WordStatPearls Publishing; updated August 28, 2023.


U.S. Food and Drug Administration (FDA). FDA approves first gene Misspelled Wordth​erapies to treat patients with sickle cell disease. FDA News Release. Silver Spring, MD; FDA; December 8, 2023.


Misspelled WordVichinsky EP. Diagnosis of sickle cell disorders. Misspelled WordUpToDate [online serial]. Waltham, MA: Misspelled WordUpToDate; October 2022.


Walters JK, Misspelled WordKrishnamurti L, Misspelled WordMapara MY, et al. Biologic and clinical efficacy of Misspelled WordLentiGlobin for sickle cell disease. N Misspelled WordEngl J Med. 2022;386(7):617-628.​

Coding

CPT Procedure Code Number(s)
N/A​
ICD - 10 Procedure Code Number(s)
N/A​
ICD - 10 Diagnosis Code Number(s)
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)
J3394     Injection, lovotibeglogene autotemcel, per treatment
Revenue Code Number(s)
N/A​

Coding and Billing Requirements

Policy History

Revisions From 08.02.15:
01/01/2025
This new policy will become effective 1/1/2025.

It has been issued to communicate the Company's position on lovotibeglogene autotemcel (Lyfgenia®)​. ​​

1/1/2025
12/30/2024
08.02.15
Medical Policy Bulletin
Commercial
No