Limitations of Use

Following treatment with LYFGENIA, patients with α-thalassemia trait (-α3.7/-α3.7) may experience anemia with erythroid dysplasia that may require chronic red blood cell transfusions [see Adverse Reactions (6.1)]. LYFGENIA has not been studied in patients with more than two α-globin gene deletions.

2.1 Dose

LYFGENIA is provided as a single dose for infusion containing a suspension of CD34+ cells in one to four infusion bags. The minimum recommended dose of LYFGENIA is 3 × 106 CD34+ cells/kg.

See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose.

2.2 Preparation Before LYFGENIA Infusion

Confirm that autologous hematopoietic stem cell (HSC) transplantation is appropriate for the patient before mobilization and apheresis and before myeloablative conditioning are initiated. Perform screening for infectious diseases, specifically human immunodeficiency virus 1 & 2 (HIV-1/HIV-2), in accordance with clinical guidelines before collection of cells for manufacturing. There are no data on use of LYFGENIA in HIV-positive patients.

2.3 Administration

LYFGENIA is for autologous use only. The patient's identity must match the patient identifiers on the LYFGENIA cassette(s) and infusion bag(s). Do not infuse LYFGENIA if the information on the patient-specific label does not match the intended patient.

• Administer LYFGENIA within 4 hours after thawing.
• Do not use an in-line blood filter or an infusion pump.

1. Before infusion, confirm that the patient's identity matches the unique patient identifiers on the LYFGENIA infusion bag(s). Use the Lot Information Sheet to confirm the total number of infusion bags to be administered.
2. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port.
3. Infuse LYFGENIA as soon as possible after thawing and complete the infusion within 4 hours.
4. Administer each infusion bag of LYFGENIA via intravenous infusion over a period of less than 30 minutes. If more than one infusion bag is provided, administer the contents of each infusion bag completely before proceeding to thaw and infuse the contents of the next infusion bag.
5. Administer the entire contents of each infusion bag to ensure that as many cells as possible are infused into the patient. After administration of each drug product, the infusion bag and any associated tubing are flushed with at least 50 mL of 0.9% sodium chloride solution to ensure as many cells as possible are infused into the patient.

5.1 Hematologic Malignancy

Hematologic malignancy has occurred in patients treated with LYFGENIA (Study 1, Group A). At the time of initial product approval, two patients treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A) developed acute myeloid leukemia (AML). One patient with α-thalassemia trait (Study 1, Group C) has been diagnosed with myelodysplastic syndrome (MDS) [see Adverse Reactions (6.1)].

The additional hematopoietic stress associated with mobilization, conditioning, and infusion of LYFGENIA, including the need to regenerate the hematopoietic system, may increase the risk of a hematologic malignancy.

Patients with sickle cell disease have an increased risk of hematologic malignancy as compared to the general population.3, 4 Patients treated with LYFGENIA may develop hematologic malignancies and should have lifelong monitoring. Monitor for hematologic malignancies with a complete blood count (with differential) at least every 6 months for at least 15 years after treatment with LYFGENIA, and integration site analysis at Months 6, 12, and as warranted.

In the event that a malignancy occurs, contact bluebird bio at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for testing.

5.2 Delayed Platelet Engraftment

Delayed platelet engraftment has been observed with LYFGENIA. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia. Two patients (4%) required more than 100 days post treatment with LYFGENIA to achieve platelet engraftment [see Adverse Reactions (6.1)].

Patients should be made aware of the risk of bleeding until platelet recovery has been achieved. Monitor patients for thrombocytopenia and bleeding according to standard guidelines. Conduct frequent platelet counts until platelet engraftment and platelet recovery are achieved. Perform blood cell count determination and other appropriate testing whenever clinical symptoms suggestive of bleeding arise.

5.3 Neutrophil Engraftment Failure

There is a potential risk of neutrophil engraftment failure after treatment with LYFGENIA. Neutrophil engraftment failure is defined as failure to achieve three consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after infusion of LYFGENIA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with LYFGENIA, provide rescue treatment with the back-up collection of CD34+ cells [see Adverse Reactions (6.1)].

5.4 Insertional Oncogenesis

There is a potential risk of lentiviral vector-mediated insertional oncogenesis after treatment with LYFGENIA.

5.5 Hypersensitivity Reactions

Allergic reactions may occur with the infusion of LYFGENIA. The dimethyl sulfoxide (DMSO) or dextran 40 in LYFGENIA may cause hypersensitivity reactions, including anaphylaxis.

5.6 Anti-retroviral Use

Patients should not take prophylactic HIV anti-retroviral medications for at least one 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 [see Dosing and Administration (2.2) and Drug Interactions (7.2)].

If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.

5.7 Hydroxyurea Use

Patients 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 [see Dosing and Administration (2.2) and Drug Interactions (7.3)].

5.8 Iron Chelation

Do not administer myelosuppressive iron chelators for 6 months post-treatment with LYFGENIA[see Dosing and Administration (2.2) and Drug Interactions (7.4)].

5.9 Interference with PCR-based Testing

Patients who have received 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, patients who have received LYFGENIA should not be screened for HIV infection using a PCR-based assay.

6.1 Clinical Trials Experience

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.

Safety was based on patients with sickle cell disease in one open-label, single-arm clinical trial and one long-term follow-up study. Of the 54 patients who initiated stem cell collection, the median (min, max) age across the studies was 25 (12, 43) years, 63% were males, 89% were Black or African American, 2% were Asian, 2% White/Caucasian and 4% were not reported. The median (min, max) duration of follow-up was 42 (12, 87) months.

Mobilization and apheresis triggered SAEs of sickle cell crisis in 6 (14%, 6/44) patients who initiated mobilization in the intent-to-treat population.

All patients who initiated conditioning (100%, 45/45) experienced at least one adverse event attributed to conditioning. The majority of conditioning-attributed events were non-serious and were consistent with the known effects of alkylating agents.

Thirty-three (73%, 33/45) patients who received LYFGENIA experienced at least one serious adverse event (SAE). Most SAEs were related to conditioning or underlying disease.

Table 1 presents the adverse drug reactions following treatment with LYFGENIA (Day 1) to Month 24.

Three patients died during LYFGENIA clinical trials; one from sudden cardiac death due to underlying disease and two from acute myeloid leukemia who were treated with an earlier version of LYFGENIA using a different manufacturing process and transplant procedure (Study 1, Group A).

7.1 Live Vaccines

Follow institutional guidelines for vaccine administration. The safety of immunization with live viral vaccines during or following LYFGENIA treatment has not been studied. Recommendations for vaccination schedules should be followed as per guidelines post-autologous hematopoietic stem cell transplant and functional asplenia.

7.2 Anti-retrovirals

Patients should not take anti-retroviral medications for at least one month prior to mobilization for required and until all cycles of apheresis are completed [see Warnings and Precautions (5.6)]. There are some long-acting anti-retroviral medications that may require a longer duration of discontinuation for elimination of the medication. Anti-retroviral medications may interfere with manufacturing of LYFGENIA.

7.3 Hydroxyurea

Patients should not take hydroxyurea for at least 2 months prior to mobilization and until all cycles of apheresis are completed and should discontinue 2 days prior to initiation of conditioning [see Warnings and Precautions (5.7)].

7.4 Iron Chelation

Drug-drug interactions between iron chelators and the mobilization process and myeloablative conditioning agent must be considered. Iron chelators should be discontinued at least 7 days prior to initiation of mobilization or conditioning. Myelosuppressive iron chelators (e.g., deferiprone) should be restarted no sooner than 6 months after LYFGENIA infusion [see Warnings and Precautions (5.8)]. Non-myelosuppressive iron chelation should be restarted no sooner than 3 months after LYFGENIA infusion. Phlebotomy can be used in lieu of iron chelation, when appropriate.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of LYFGENIA have been established in pediatric patients 12 years of age and older with sickle cell disease, including 8 adolescents (age 12 years to less than 18) [see Clinical Studies (14)].

No clinically meaningful differences in efficacy or safety were observed between the adult and pediatric subgroups.

The safety and efficacy of LYFGENIA in children less than 12 years of age have not been established. No data are available.

8.5 Geriatric Use

LYFGENIA has not been studied in patients 65 years of age and older. Autologous hematopoietic stem cell (HSC) transplantation must be appropriate for a patient to be treated with LYFGENIA.

8.6 Patients Seropositive for Human Immunodeficiency Virus (HIV)

LYFGENIA has not been studied in patients with HIV-1 or HIV-2. A negative serology test for HIV is necessary prior to apheresis. Patients with a positive test for HIV will not be accepted for LYFGENIA treatment.

8.7 Renal Impairment

LYFGENIA has not been studied in patients with renal impairment (defined as creatinine clearance ≤ 70 mL/min/1.73 m2). Patients' renal function should be assessed for renal impairment to ensure autologous HSC transplantation is appropriate.

8.8 Hepatic Impairment

LYFGENIA has not been studied in patients with advanced hepatic disease. Patients' hepatic function should be assessed for hepatic impairment to ensure autologous HSC transplantation is appropriate.

12.1 Mechanism of Action

LYFGENIA adds functional copies of a modified βA-globin gene (threonine [T] replaced with glutamine [Q] at position 87, T87Q or βA-T87Q-globin) into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with BB305 LVV. After LYFGENIA infusion, the transduced CD34+ HSCs engraft in the bone marrow and differentiate to produce red blood cells containing biologically active βA-T87Q-globin that will combine with α-globin to produce functional Hb containing βA-T87Q-globin (HbAT87Q). βA-T87Q-globin can be distinguished from wildtype βA-globin and from βS-globin through reverse-phase high-performance liquid chromatography (RPHPLC) or ultra-high performance liquid chromatography (UPLC). HbAT87Q has similar oxygen-binding affinity and oxygen hemoglobin dissociation curve to wild type HbA, reduces intracellular and total hemoglobin S (HbS) levels, and is designed to sterically inhibit polymerization of HbS thereby limiting the sickling of red blood cells.

12.2 Pharmacodynamics

HbAT87Q generally increased steadily after LYFGENIA infusion and stabilized by approximately Month 6 after infusion. Patients had a Month 6 median (min, max) HbAT87Q of 5.2 (2.6, 8.8) g/dL in an ongoing Phase 1/2 Study Group C (Study 1-C) (N = 33). HbAT87Q remained durable with a median (min, max) of 5.5 (2.4, 9.4) g/dL at Month 24 (N = 34). HbAT87Q comprised a median (min, max) 45.7 (26.9, 63.2) (N = 34) percent of total non-transfused Hb at Month 24.

Expression of HbAT87Q continued to remain durable through Month 48 (N = 10), demonstrating sustained expression of the βA-T87Q protein derived from irreversible integration of the βA-T87Q-globin gene into long-term hematopoietic stem cells (HSCs).

12.3 Pharmacokinetics

LYFGENIA is an autologous gene therapy which includes hematopoietic stem cells (HSCs) that have been genetically modified ex vivo. The nature of LYFGENIA is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been performed with LYFGENIA.

No studies have been conducted to evaluate the effects of LYFGENIA on fertility.

Efficacy Outcomes

The transplant population for VOE efficacy outcomes included patients with a history of at least 4 VOEs in the 24 months prior to informed consent. The efficacy outcomes were complete resolution of VOEs (VOE-CR) and severe VOEs (sVOE-CR) between 6 months and 18 months after infusion of LYFGENIA.

VOEs were defined as any of the following events requiring evaluation at a medical facility:

• an episode of acute pain with no medically determined cause other than vaso-occlusion, lasting more than 2 hours
• acute chest syndrome (ACS)
• acute hepatic sequestration
• acute splenic sequestration

Severe VOE (sVOE) were defined as either of the following events:

• VOE requiring a hospitalization or multiple visits to an emergency department/urgent care over 72 hours and receiving intravenous medications at each visit
• priapism requiring any level of medical attention

Globin response (GR) was defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion:

• weighted average hemoglobin AT87Q percentage of non-transfused total Hb ≥ 30% AND
• weighted average non-transfused total Hb (HbS+HbF+HbA2+HbAT87Q) increase of ≥ 3 g/dL compared to baseline total Hb OR weighted average non-transfused total Hb ≥ 10 g/dL.

All 36 patients infused in Study 1-C (transplant population) were evaluated for globin response. 31/36 (86%) achieved GR. All patients maintained GR once it was achieved.

The median (min, max) duration of follow-up for the patients in Study 1-C (N = 36) is 38 (12, 61) months post LYFGENIA infusion. After the primary evaluation period to last follow-up, 4 of 32 patients who achieved VOE-CR experienced VOEs while maintaining GR. After the primary evaluation period up to 24 months, 17 of 35 (49%) patients were prescribed opioids for sickle cell and non-sickle cell-related pain.

Neurologic outcome

Five patients with history of stroke or vasculopathy were treated on Study 1-C. All were at least 18 years old and on chronic transfusion therapy prior to LYFGENIA infusion. At 44-60 months follow up, all five subjects remain transfusion independent without recurrent stroke.

Match the identity of the patient with the patient identifiers on the metal cassette(s), infusion bag(s), and Lot Information Sheet upon receipt.

• Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at less than or equal to -140°C (≤ -220°F) until ready for thaw and administration.
• Thaw LYFGENIA prior to infusion [see Dosage and Administration (2.2)].
• Do not re-freeze after thawing.
• Do not irradiate LYFGENIA, as this could lead to inactivation.