Drug Detail:Skysona (Elivaldogene autotemcel)
Drug Class: Miscellaneous uncategorized agents
Highlights of Prescribing Information
SKYSONA (elivaldogene autotemcel) suspension for intravenous infusion
Initial U.S. Approval: 2022
WARNING: HEMATOLOGIC MALIGNANCY
See full prescribing information for complete boxed warning.
Hematologic malignancy, including life-threatening cases of myelodysplastic syndrome, has occurred in patients treated with SKYSONA. The cancers appear to be the result of the SKYSONA lentiviral vector, Lenti-D, integration in proto-oncogenes. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through assessments for evidence for clonal expansion or predominance at least twice in the first year and annually thereafter; consider bone marrow evaluations as clinically indicated. (5.1)
Indications and Usage for Skysona
SKYSONA is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Early, active CALD refers to asymptomatic or mildly symptomatic (neurologic function score, NFS ≤ 1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9.
This indication is approved under accelerated approval based on 24-month Major Functional Disability (MFD)-free survival. [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). (1)
Limitations of Use
- SKYSONA does not treat or prevent adrenal insufficiency. (1)
- An immune response to SKYSONA may cause rapid loss of efficacy of SKYSONA in patients with full deletions of the human adenosine triphosphate binding cassette, sub family D, member 1 (ABCD1) gene. (1)
- SKYSONA has not been studied in CALD secondary to head trauma. (1)
- Given the risk of hematologic malignancy with SKYSONA, and unclear long-term durability of SKYSONA and human adrenoleukodystrophy protein (ALDP) expression, careful consideration should be given to the timing of treatment for each boy and treatment of boys with isolated pyramidal tract disease as clinical manifestations do not usually occur until adulthood. (1)
Skysona Dosage and Administration
For autologous use only. For intravenous use only.
- Patients must undergo hematopoietic stem cell (HSC) mobilization and apheresis to obtain CD34+ cells for SKYSONA manufacturing. (2.2)
- Dosing of SKYSONA is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight. (2.1)
- The minimum recommended dose is 5.0 × 106 CD34+ cells/kg. (2.1)
- Full myeloablative and lymphodepleting conditioning must be administered before infusion of SKYSONA. (2.2)
- Verify the patient's identity matches the unique patient identification information on the SKYSONA infusion bag(s) prior to infusion. (2.2)
- Do not sample, alter, or irradiate SKYSONA. (2.2)
- Do not use an in-line blood filter or an infusion pump. (2.3)
Dosage Forms and Strengths
- SKYSONA is a cell suspension for intravenous infusion. (3)
- A single dose of SKYSONA contains a minimum of 5.0 × 106 CD34+ cells/kg of body weight, suspended in a solution containing 5% dimethyl sulfoxide (DMSO). (3)
Contraindications
None. (4)
Warnings and Precautions
- Serious Infections: Life-threatening bacterial and viral infections may occur. Monitor patients for signs and symptoms of infection. (5.2)
- Prolonged Cytopenias: Patients may exhibit cytopenias >1 year after treatment with SKYSONA. Monitor patients for bleeding and infection. (5.3)
- Delayed Platelet Engraftment: Monitor patients for thrombocytopenia and bleeding until platelet engraftment and count recovery. (5.4)
- Risk of Neutrophil Engraftment Failure: Monitor absolute neutrophil counts and if neutrophil engraftment does not occur, give rescue cells. (5.5)
Adverse Reactions/Side Effects
- Most common non-laboratory adverse reactions (≥ 20%): mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, rash. (6.1)
- Most common Grade 3 or 4 laboratory abnormalities (≥40%): leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, hypokalemia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact bluebird bio at 1-833-999-6378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
Anti-retrovirals: Do not take anti-retroviral medications for at least one month prior to initiating medications for stem cell mobilization and for the expected duration for elimination of the medications, and until all cycles of apheresis are complete. (7.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 9/2022
Full Prescribing Information
WARNING: HEMATOLOGIC MALIGNANCY
Hematologic malignancy, including life-threatening cases of myelodysplastic syndrome, has occurred in patients treated with SKYSONA. Patients have been diagnosed between 14 months and 7.5 years after SKYSONA administration, and the cancers appear to be the result of the SKYSONA lentiviral vector, Lenti-D, integration in proto-oncogenes. Monitor patients closely for evidence of malignancy through complete blood counts at least every 6 months and through assessments for evidence for clonal expansion or predominance at least twice in the first year and annually thereafter; consider bone marrow evaluations as clinically indicated [see Warnings and Precautions (5.1)].
1. Indications and Usage for Skysona
SKYSONA is indicated to slow the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy (CALD). Early, active cerebral adrenoleukodystrophy refers to asymptomatic or mildly symptomatic (neurologic function score, NFS ≤ 1) boys who have gadolinium enhancement on brain magnetic resonance imaging (MRI) and Loes scores of 0.5-9.
This indication is approved under accelerated approval based on 24-month Major Functional Disability (MFD)-free survival [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).
2. Skysona Dosage and Administration
For autologous use only. For intravenous use only.
2.1 Dose
SKYSONA is provided as a single dose for infusion containing a suspension of CD34+ cells in one or two infusion bags. The minimum recommended dose of SKYSONA is 5.0 × 106 CD34+ cells/kg.
The dose is calculated based on the patient's weight prior to first apheresis. See the Lot Information Sheet provided with the product shipment for additional information pertaining to dose.
2.2 Preparation Before SKYSONA Infusion
Before mobilization, apheresis, and conditioning are initiated, confirm that hematopoietic stem cell (HSC) transplantation is appropriate for the patient.
Perform screening for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus 1 & 2 (HIV-1/HIV-2) and Human T-lymphotropic virus 1 & 2 (HTLV-1/HTLV-2) in accordance with clinical guidelines before collection of cells for manufacturing.
2.3 Administration
SKYSONA is for autologous use only. The patient's identity must match the patient identifiers on the SKYSONA cassette(s) and infusion bag(s). Do not infuse SKYSONA if the information on the patient-specific label does not match the intended patient.
- Do not use an in-line blood filter or an infusion pump.
- Before infusion, confirm that the patient's identity matches the unique patient identifiers on the SKYSONA infusion bag(s). The total number of infusion bags to be administered should also be confirmed with the Lot Information Sheet.
- Prime the tubing of the infusion set with 0.9% sodium chloride solution prior to infusion.
- Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port.
- Access the SKYSONA infusion bag and infuse per the treatment center's standard procedures for administration of cell therapy products.
- Complete the infusion of SKYSONA as soon as possible, and no more than 4 hours after thawing.
- Administer each infusion bag of SKYSONA via intravenous infusion (drip) by gravity flow over a period of less than 60 minutes.
- After the entire content of the infusion bag is infused, flush all SKYSONA remaining in the infusion bag and any associated tubing with at least 50 mL of 0.9% sodium chloride solution to ensure that as many cells as possible are infused into the patient.
- If more than one infusion bag is provided, administer each infusion bag completely before proceeding to thaw (following Section 2.2 steps 7-8) and infuse (following Section 2.3 steps 2-6) the next infusion bag.
3. Dosage Forms and Strengths
SKYSONA is a cell suspension for intravenous infusion.
SKYSONA is composed of one or two infusion bags which contain 4 to 30 × 106 cells/mL suspended in cryopreservation solution [see How Supplied/Storage and Handling (16)]. Each infusion bag contains approximately 20 mL of SKYSONA. A single dose of SKYSONA contains a minimum of 5.0 × 106 CD34+ cells per kg of body weight, suspended in cryopreservation solution.
See the Lot Information Sheet for actual dose.
5. Warnings and Precautions
5.1 Hematologic Malignancy
Myelodysplastic syndrome (MDS), a hematologic malignancy, has developed in patients treated with SKYSONA in clinical studies. At the time of initial product approval, MDS had been diagnosed in three patients after administration of SKYSONA. The clinical presentation for the three patients varied. Two patients who were diagnosed at 14 months and 2 years after treatment with SKYSONA had preceding delayed platelet engraftment. The third patient had normal blood counts from 18 months to 5 years following treatment with SKYSONA and presented 7.5 years after SKYSONA administration with symptomatic anemia and thrombocytopenia and was subsequently diagnosed with MDS with increased blasts. All 3 patients underwent allogeneic hematopoietic stem cell transplant; 1 patient required pre-transplant chemotherapy and total body irradiation as treatment for excess blasts prior to transplant and 1 patient underwent total body irradiation as part of his conditioning regimen [see Adverse Reactions (6.1)].
SKYSONA Lenti-D lentiviral vector integration into proto-oncogenes appears to have mediated the three cases of hematologic malignancy. The hematologic malignancies diagnosed at 14 months and 2 years involved integration into the MECOM proto-oncogene and increased expression of the oncoprotein EVI1. All patients treated with SKYSONA in clinical studies have integrations into MECOM; it is unknown which integrations into MECOM or other proto-oncogenes are likely to lead to malignancy.
Because of the risk of hematologic malignancy, carefully consider alternative therapies prior to the decision to treat a child with SKYSONA. Consider consultation with hematology experts prior to SKYSONA treatment to inform benefit-risk treatment decision and to ensure adequate monitoring for hematologic malignancy. Consider performing the following baseline hematologic assessments: complete blood count with differential, hematopathology review of peripheral blood smear, and bone marrow biopsy (core and aspirate) with flow cytometry, conventional karyotyping, and next generation sequencing (NGS) with a molecular panel appropriate for age and including coverage for gene mutations expected in myeloid and lymphoid malignancies; and testing for germline mutations that are associated with hematologic malignancy.
Early diagnosis of hematologic malignancy can be critically important, therefore, monitor patients treated with SKYSONA lifelong for hematologic malignancy. For the first fifteen years after treatment with SKYSONA, monitor via complete blood count (with differential) at least twice per year and via integration site analysis or other testing for evidence of clonal expansion and predominance at least twice in the first year and then annually. Consider appropriate expert consultation and additional testing such as more frequent complete blood count (with differential) and integration site analysis, bone marrow studies, and gene expression studies in the following settings after treatment with SKYSONA:
- Delayed or failed engraftment of platelets or other cell lines (patients who do not achieve unsupported platelet counts of ≥ 20 × 109/L on or after Day 60 appear to be at particularly high risk for developing malignancy); or
- New or prolonged cytopenias; or,
- Presence of clonal expansion or predominance (e.g., increasing relative frequency of an integration site, especially if ≥ 10% and present in MECOM or another proto-oncogene known to be involved in hematologic malignancy).
If hematologic malignancy is detected in a patient who received SKYSONA, contact bluebird bio at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for further testing.
5.2 Serious Infections
Severe infections, including life-threatening or fatal infections, have occurred in patients after SKYSONA infusion. Important opportunistic infections that have been diagnosed within the first 3 months after treatment with SKYSONA include BK cystitis, cytomegalovirus reactivation, human herpesvirus-6 viremia, candidiasis, and bacteremias. Opportunistic infections after the first 3 months include an atypical mycobacterium vascular device infection, pseudomonas bacteremia, and Epstein-Barr virus reactivations diagnosed as late as 18 months after treatment with SKYSONA. Serious infections involving adenovirus include a case of transverse myelitis at 6 months that was attributed to adenovirus and entero/rhinovirus infection, and a fatal adenovirus infection at 21 months in a patient with CALD progression who developed multisystem organ failure.
Grade 3 or higher infections occurred in 21% of all patients (12% bacterial, 3% viral, and 6% unspecified). The most common Grade 3 or higher infections were vascular device infections (7% of patients) diagnosed as late as 6 months after treatment with SKYSONA, and bacteremias (6% of patients) diagnosed as late as 8 months after treatment with SKYSONA.
Febrile neutropenia developed within two weeks after SKYSONA infusion in 72% of patients. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.
Monitor patients for signs and symptoms of infection before and after SKYSONA administration and treat appropriately. Administer prophylactic antimicrobials according to best clinical practices and clinical guidelines.
Avoid administration of SKYSONA in patients with active infections.
5.3 Prolonged Cytopenias
Patients may exhibit cytopenias, including pancytopenia, for > 1 year following conditioning and SKYSONA infusion [see Adverse Reactions (6.1)].
Grade 3 or higher cytopenias on or after Day 60 following SKYSONA infusion occurred in 47% of patients and included low platelet count (14%), low neutrophil count (22%), low lymphocyte count (27%), and low hemoglobin (2%). Grade 3 cytopenias persisted beyond Day 100 in 15% of patients and included low platelet count (7%), low neutrophil count (9%), and low lymphocyte count (6%).
Serious adverse reactions of pancytopenia occurred in two patients who required support with blood and platelet transfusions as well as growth factors (G-CSF for up to 6 months and eltrombopag for up to 14 months) after SKYSONA administration. One patient had intercurrent parvovirus infection and his pancytopenia was ongoing at least two years after SKYSONA administration. Pancytopenia in the other patient was ongoing until he was diagnosed with myelodysplastic syndrome approximately two years after SKYSONA administration.
Monitor blood counts until normalization and assess patients for signs and symptoms of bleeding and/or infection prior to and after SKYSONA administration.
5.4 Delayed Platelet Engraftment
Delayed platelet engraftment has been observed with SKYSONA [see Adverse Reactions (6.1)]. Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia; 14% of patients had a platelet count ≤ 50 × 109/L beyond 60 days after treatment with SKYSONA.
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.
5.5 Risk of Neutrophil Engraftment Failure
There is a potential risk of neutrophil engraftment failure after treatment with SKYSONA. Neutrophil engraftment failure was defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) ≥ 0.5 × 109 cells/L obtained on different days by Day 43 after infusion of SKYSONA. Monitor neutrophil counts until engraftment has been achieved. If neutrophil engraftment failure occurs in a patient treated with SKYSONA, provide rescue treatment with the back-up collection of CD34+ cells [see Adverse Reactions (6.1)].
5.6 Hypersensitivity Reactions
Allergic reactions may occur with the infusion of SKYSONA. The dimethyl sulfoxide (DMSO) in SKYSONA may cause hypersensitivity reactions, including anaphylaxis which is potentially life-threatening and requires immediate intervention.
5.7 Anti-retroviral Use
Patients should not take anti-retroviral medications for at least one month prior to mobilization or the expected duration for elimination of the medications, and until all cycles of apheresis are completed. Anti-retroviral medications may interfere with manufacturing of the apheresed cells [see Drug Interactions (7.2)].
If a patient requires anti-retrovirals for HIV prophylaxis, mobilization and apheresis of CD34+ cells should be delayed until HIV infection is adequately ruled out.
6. Adverse Reactions/Side Effects
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Hematologic Malignancy [see Warnings and Precautions (5.1)]
- Serious Infections [see Warnings and Precautions (5.2)]
- Prolonged Cytopenias [see Warnings and Precautions (5.3)]
- Delayed Platelet Engraftment [see Warnings and Precautions (5.4)]
- Risk of Neutrophil Engraftment Failure [see Warnings and Precautions (5.5)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
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.
The safety data described in this section reflect exposure to a single dose of SKYSONA in 67 patients with CALD. Data were obtained from two single-arm trials and, for 36 patients, from a long-term follow-up study [see Clinical Studies (14)]. The median (min, max) age across studies was 6 (4, 14) years; 100% were male; 54% were White/Caucasian, 4% were Black or African American, 1% were Asian, 10% were of other races including mixed race, and 30% did not report race; 25% were of Hispanic ethnicity. The median (min, max) duration of follow-up is 24 (1, 88) months.
In the two trials, serious adverse reactions from Day 1 (SKYSONA infusion) to last follow-up occurred in 54% of patients. The most common non-laboratory, serious adverse reactions (≥ 3% incidence) that occurred after treatment with SKYSONA were febrile neutropenia (18%), pyrexia (fever) (18%), seizure (7%), myelodysplastic syndrome (4%), pseudomonal bacteremia (3%), pancytopenia (3%), vascular device infection (3%), mucositis (3%), and vomiting (3%).
Most common non-laboratory adverse reactions by time of onset follow:
- During mobilization and conditioning and occurring in ≥ 20% of patients: nausea (79%), vomiting (72%), decreased appetite (42%), catheter site pain (39%), constipation (30%), headache (24%), abdominal pain (21%), rash (13%)
- In the first 60 days after treatment with SKYSONA in ≥ 15% of patients: mucositis (88%), febrile neutropenia (73%), alopecia (72%), abdominal pain (33%), vomiting (31%), decreased appetite (31%), pyrexia (27%), nausea (27%), constipation (21%), diarrhea (21%), epistaxis (19%), pruritus (18%), headache (16%), oropharyngeal pain (16%), skin hyperpigmentation (16%), anxiety (15%)
- Between 60 days and 1 year after treatment with SKYSONA in ≥ 5% of patients: pyrexia (fever) (9%) and vomiting (6%)
- At least 1 year after treatment with SKYSONA in ≥ 5% of patients: seizure (15%) and myelodysplastic syndrome (6%)
Table 1 presents non-laboratory adverse reactions reported in at least 10% of patients between the start of conditioning and 24 months after SKYSONA administration. Table 2 presents Grade 3 or 4 laboratory abnormalities that occurred in at least 40% of patients between the start of conditioning and 24 months after SKYSONA administration.
Adverse Reaction | Any Grade N (%) | Grade 3 or Higher N (%) |
---|---|---|
|
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Blood and lymphatic system disorders | -- | -- |
Febrile neutropenia† | 49 (73%) | 49 (73%) |
Cardiac disorders | -- | -- |
Tachycardia‡ | 10 (15%) | 0 |
Eye disorders | -- | -- |
Vision blurred | 7 (10%) | 0 |
Gastrointestinal disorders | -- | -- |
Mucositis§¶ | 62 (92%) | 34 (51%) |
Nausea | 56 (84%) | 17 (25%) |
Vomiting | 51 (76%) | 12 (18%) |
Abdominal pain# | 30 (45%) | 2 (3%) |
Constipation | 28 (42%) | 0 |
Diarrhea | 19 (28%) | 1 (1%) |
General disorders and administration site conditions | -- | -- |
Pyrexia | 24 (36%) | 3 (4%) |
Injury, poisoning and procedural complications | -- | -- |
Transfusion reactionÞ | 8 (12%) | 2 (3%) |
Metabolism and nutrition disorders | -- | -- |
Decreased appetite | 43 (64%) | 27 (40%) |
Nervous system disorders | -- | -- |
Headache | 19 (28%) | 0 |
Anxiety߶ | 10 (15%) | 0 |
Respiratory, thoracic, and mediastinal disorders | -- | -- |
Epistaxis | 13 (19%) | 5 (7%) |
Oropharyngeal painච| 12 (18%) | 3 (4%) |
Cough | 7 (10%) | 0 |
Skin and subcutaneous tissue disorders | -- | -- |
Alopecia | 48 (72%) | 1 (1%) |
Rashè | 14 (21%) | 0 |
Pruritusð¶ | 13 (19%) | 0 |
Skin hyperpigmentation | 12 (18%) | 0 |
Vascular disorders | -- | -- |
Hypertension | 8 (12%) | 1 (1%) |
Laboratory Abnormality | Grade 3 or 4 N (%) |
---|---|
|
|
Leukopenia | 67 (100%) |
Lymphopenia | 67 (100%) |
Thrombocytopenia | 67 (100%) |
Neutropenia | 64 (96%) |
Anemia | 56 (84%) |
Hypokalemia | 28 (42%) |
7. Drug Interactions
7.1 Vaccines
The safety and effectiveness of vaccination during or following SKYSONA treatment have not been studied. Vaccination is not recommended during the 6 weeks preceding the start of myeloablative conditioning, and until hematological recovery following treatment with SKYSONA. Where feasible, administer childhood vaccinations prior to myeloablative conditioning for SKYSONA.
7.2 Anti-retrovirals
Patients should not take anti-retroviral medications for at least one month prior to initiating medications for stem cell mobilization and for the expected duration for elimination of the medications, and until all cycles of apheresis are completed [see Warnings and Precautions (5.5)].
Anti-retroviral medications may interfere with SKYSONA manufacture.
8. Use In Specific Populations
8.4 Pediatric Use
The safety and efficacy of SKYSONA in children less than 4 years of age have not been established. No data are available [see Clinical Studies (14)].
8.6 Patients with a Full ABCD1 Gene Deletion
In the only patient in the SKYSONA clinical studies who had a full ABCD1 deletion, disease progression occurred. The patient experienced radiologic disease progression in the setting of declining peripheral blood vector copy number, suggesting loss of product efficacy which may have been immune mediated. The patient was subsequently treated with allogeneic hematopoietic stem cell transplant.
8.7 Renal Impairment
SKYSONA has not been studied in patients with renal impairment. Patients should be assessed for renal impairment to ensure hematopoietic stem cell (HSC) transplantation is appropriate.
8.8 Hepatic Impairment
SKYSONA has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.
8.9 Patients Seropositive for Human Immunodeficiency Virus (HIV)
SKYSONA has not been studied in patients with HIV-1, HIV-2, HTLV-1, or HTLV-2. A negative serology test for HIV is necessary to ensure acceptance of apheresis material for SKYSONA manufacturing. Apheresis material from patients with a positive test for HIV will not be accepted for SKYSONA manufacturing.
11. Skysona Description
SKYSONA (elivaldogene autotemcel) is an autologous HSC-based gene therapy prepared from the patient's HSCs, which are collected via apheresis procedure(s). The autologous cells are enriched for CD34+ cells, then transduced ex vivo with Lenti-D LVV, and cultured with growth factors overnight. Lenti-D LVV is a replication-incompetent, self-inactivating LVV carrying ABCD1 cDNA that encodes normal ALDP. The ABCD1 gene is under the control of an internal MNDU3 promoter, which is a modified viral promoter and has been shown to control expression of the transgene in HSCs and their progeny in all lineages.
The transduced CD34+ cells are washed, formulated into a suspension, and then cryopreserved. SKYSONA is frozen in a patient-specific infusion bag(s) and is thawed prior to administration [see Dosage and Administration (2.1), How Supplied/Storage and Handling (16)]. The thawed product is colorless to white to red, including shades of white or pink, light yellow, and orange suspension of cells and may contain small proteinaceous particles. Due to the presence of cells, the solution may be clear to slightly cloudy and may contain visible cell aggregates.
The formulation contains 5% dimethyl sulfoxide (DMSO).
12. Skysona - Clinical Pharmacology
12.1 Mechanism of Action
SKYSONA adds functional copies of the ABCD1 cDNA into patients' hematopoietic stem cells (HSCs) through transduction of autologous CD34+ cells with Lenti-D LVV. After SKYSONA infusion, transduced CD34+ HSCs engraft in the bone marrow and differentiate into various cell types, including monocytes (CD14+) capable of producing functional ALDP. Functional ALDP can then participate in the local degradation of very long chain fatty acids (VLCFAs), which is believed to slow or possibly prevent further inflammation and demyelination.
12.2 Pharmacodynamics
All patients who received SKYSONA with at least 1 month of follow-up produced ALDP in CD14+ cells (N=23, Study 1; N=31, Study 2), demonstrating early expression of the transgene. The %ALDP+ cell counts stabilized at 6 months after SKYSONA infusion. Patients had a Month 6 median (min, max) %ALDP+ CD14+ cells of 16% (2%, 71%) in Study 1 (N=23) and 26% (2%, 86%) in Study 2 (N=25).
In peripheral blood, the %ALDP+ CD14+ cells remained generally stable through Month 24 with a median (min, max) of 15% (6%, 45%) in Study 1 (N=23) and 28% (2%, 40%) in Study 2 (N=11). ALDP expression was quantifiable in 43% of the patients who had follow-up through Month 60 in Study 1 (N=7), indicating long-term expression of transgenic ALDP in the progeny of hematopoietic stem cells.
14. Clinical Studies
The safety and efficacy of SKYSONA were assessed in two 24-month, open-label, single-arm studies in patients with early, active CALD as defined by Loes score between 0.5 and 9 (inclusive) and gadolinium enhancement (GdE+) on MRI, as well as a neurologic function score (NFS) of ≤ 1, indicating limited changes in neurologic function. The NFS was used to evaluate 15 domains of neurological function with a maximum score of 25. A total NFS=0 indicates absence of neurologic dysfunction or asymptomatic disease. The patients enrolled and treated with SKYSONA (Study 1, N=32; Study 2, N=35) all had elevated very long chain fatty acid (VLCFA) levels and confirmed mutations in the ABCD1 gene. Following completion of Study 1 and Study 2, patients enroll in a subsequent and ongoing long-term follow-up study. The efficacy of SKYSONA was compared to an external untreated natural history control. Data for the Natural History Population in the retrospective natural history study (Study 3) was collected from existing medical records for patients with CALD. The Natural History Population had early, active disease at diagnosis, though gadolinium status was defined by either having a GdE+ MRI during the study or unknown GdE status and clinical course that suggested active disease.
16. How is Skysona supplied
SKYSONA is supplied in one or two infusion bags containing a frozen suspension of genetically modified autologous cells enriched for CD34+ cells. Each bag contains approximately 20 mL. Each SKYSONA infusion bag is individually packed within an overwrap in a metal cassette. SKYSONA is shipped from the manufacturing facility to the infusion center in a cryoshipper, which may contain multiple metal cassettes intended for treatment of a single patient. A Lot Information Sheet is affixed inside the shipper.
- 20 mL infusion bag, overwrap, and metal cassette (NDC 73554-2111-1)
SKYSONA
elivaldogene autotemcel suspension |
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Labeler - bluebird bio, Inc. (969116102) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Lonza Houston, Inc. | 832903004 | ANALYSIS(73554-2111) , LABEL(73554-2111) , MANUFACTURE(73554-2111) , PACK(73554-2111) , API MANUFACTURE(73554-2111) |