Get your patient on Skysona (Elivaldogene Autotemcel)

Limitations of Use

SKYSONA does not prevent the development of or treat adrenal insufficiency due to adrenoleukodystrophy.

An immune response to SKYSONA may limit the persistence of descendent cells of SKYSONA, causing 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.

SKYSONA has not been studied in patients with CALD secondary to head trauma.

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 appropriateness and timing of treatment for each boy, especially for boys with isolated pyramidal tract disease since their clinical symptoms do not usually occur until adulthood.

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 × 10 ⁶ 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.

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.

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.

1. 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.
2. Prime the tubing of the infusion set with 0.9% sodium chloride solution prior to infusion.
3. Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port.
4. Access the SKYSONA infusion bag and infuse per the treatment center's standard procedures for administration of cell therapy products.
5. Complete the infusion of SKYSONA as soon as possible, and no more than 4 hours after thawing.
6. Administer each infusion bag of SKYSONA via intravenous infusion (drip) by gravity flow over a period of less than 60 minutes.
7. 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.
8. 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.

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) ] .

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.

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.

SKYSONA has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure HSC transplantation is appropriate.

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.

Hematologic malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), have developed in patients treated with SKYSONA in clinical studies between 14 months and 10 years after SKYSONA administration [see Adverse Reactions (6.1) ] . Malignancies are life-threatening. Death related to treatment for malignancy and relapse of malignancy have occurred .

SKYSONA Lenti-D lentiviral vector genomic integration, including into the proto-oncogene MECOM , appears to have mediated the cases of hematologic malignancy. All patients treated with SKYSONA in clinical studies have integrations into MECOM ; however, it is unknown which integrations into MECOM or other genes are likely to lead to malignancy.

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 at least the first fifteen years after treatment with SKYSONA, monitor via complete blood count (with differential) at least every 3 months 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 (while all patients are at risk for hematologic malignancy, patients who do not achieve unsupported platelet counts of ≥ 20 × 10 ⁹ /L on or after Day 60 appear to be at higher risk); 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 Genetix Biotherapeutics at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for further testing.

Severe infections, including life-threatening and fatal infections, have occurred in patients after SKYSONA infusion.

Febrile neutropenia was commonly observed in clinical studies and may be a sign of a serious infection. 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.

Patients may exhibit cytopenias, including pancytopenia, for > 1 year following conditioning and SKYSONA infusion [see Adverse Reactions (6.1) ] .

Monitor blood counts until normalization and assess patients for signs and symptoms of bleeding and/or infection prior to and after SKYSONA administration.

Delayed platelet engraftment (platelet count ≤ 50 × 10 ⁹ /L beyond 60 days after treatment with SKYSONA) has been observed [see Adverse Reactions (6.1) ] . Bleeding risk is increased prior to platelet engraftment and may continue after engraftment in patients with prolonged thrombocytopenia.

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.

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 × 10 ⁹ 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) ] .

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.

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.

SKYSONA affects polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion. A PCR-based assay should not be used to screen for HIV infection in patients treated with SKYSONA as a false-positive test result is likely.

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 at time of initial approval was 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%)

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.

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.

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.

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.

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.

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

No carcinogenicity studies have been performed with SKYSONA. No studies have been conducted to evaluate the effects of SKYSONA on fertility.

SKYSONA Studies

Study 1 is complete and Study 2 is ongoing at the time of product approval. In Study 1, patients were 47% White/Caucasian, 38% Hispanic, 3% Asian, 3% Black or African American, and 16% other races including mixed race. In Study 2, patients were 60% White/Caucasian, 14% Hispanic, 6% Black or African American, 6% other races including mixed race.

Mobilization and Apheresis:

• G-CSF 10 µg/kg (median) for a minimum of 4 days
• Plerixafor 0.24 mg/kg for up to 3 days – optional in Study 1 (administered to 34% of patients) and required in Study 2

For all patients, one cycle of mobilization and apheresis and one to two apheresis collection days were sufficient to obtain the requisite number of cells needed for manufacturing.

Pre-treatment Myeloablative Conditioning:

• Study 1: Busulfan dose median (min, max) 14 (11.2 to 16.8) mg/kg over 4 days
• Study 2: Busulfan dose median (min, max) 16.8 (12 to 21.2) mg/kg over 4 days

Pre-treatment Lymphodepletion:

• Study 1: Cyclophosphamide dose median (min, max) 199 (151 to 213) mg/kg over 4 days
• Study 2: Fludarabine dose 180 mg/m ² over 6 days for 11 patients; 160 mg/m ² over 4 days (actual dose range 122 to 196 mg/m ² ) for 24 patients; (fludarabine dose decreased due to viral infections in the initial cohort)

Patients received seizure, hepatic veno-occlusive disease, anti-fungal, and antibiotic prophylaxis in accordance with institutional guidelines.

SKYSONA Administration:

• All patients were administered SKYSONA as an intravenous infusion with a median (min, max) dose of 12 × 10 ⁶ (5, 38.2) CD34+ cells/kg (N=67).

After SKYSONA Administration:

• G-CSF – optional in Study 1 (administered to 75% of patients) and required in Study 2 (beginning on Day 5)
• See Section 6 for engraftment information.

Comparison of SKYSONA with the Natural History of CALD

A post-hoc enrichment analysis in symptomatic patients compared time from onset of symptoms (NFS ≥ 1) to time to first Major Functional Disability (MFD) or death (i.e., MFD-free survival) in SKYSONA treated and Natural History patients. The MFDs are defined as: loss of communication, cortical blindness, requirement for tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement. To be included in the analysis, patients had to have symptoms at baseline (NFS=1) or be asymptomatic (NFS=0) at baseline and have developed symptoms (NFS ≥ 1) during the course of follow-up in the study. Additionally, they had to have at least 24 months of follow-up after initial NFS ≥ 1 or have had an event (MFD or death).

The 7 patients in the Natural History Population were a median (min, max) 9 (5, 15) years old at time of CALD diagnosis, and 10 (5, 17) years at time of first NFS ≥ 1. The median Loes score at diagnosis was 5 (2, 9). Four (57%) had a baseline brain MRI pattern of disease inclusive of parieto-occipital involvement, 2 (29%) had frontal disease (without parieto-occipital involvement) and 1 (14%) had isolated pyramidal tract disease. One (14%) had a baseline NFS=1 at diagnosis, and the remainder were asymptomatic (NFS=0) at diagnosis.

The symptomatic SKYSONA subpopulation (N=11) had baseline median (min, max) age at treatment of 6 (4, 10) years, age at first NFS ≥ 1 of 7 (4, 10) years, and a baseline Loes score of 2.5 (1, 9). Ten (91%) patients had a parieto-occipital pattern of disease on brain MRI and 1 (9%) had isolated pyramidal tract disease. At baseline, 2 (18%) patients had an NFS=1 and the remainder were asymptomatic (NFS=0) prior to treatment.

Slower progression to MFD or death from time of symptom onset (first NFS ≥ 1) was seen for early, active CALD patients treated with SKYSONA compared to a similar natural history of disease (Figure 1). Kaplan-Meier (KM) estimated MFD-free survival at Month 24 from time of first NFS ≥ 1 were 72% (95% CI: 35%, 90%) for the symptomatic SKYSONA subpopulation and 43% (95% CI: 10%, 73%) for the Natural History Population. There were insufficient data beyond 24 months for the symptomatic SKYSONA subpopulation to assess long-term MFD-free survival as compared to the natural history of disease. There was insufficient duration of follow-up to assess efficacy in SKYSONA treated patients who remained asymptomatic.

Figure 1 Kaplan-Meier Curve of MFD-free Survival in Symptomatic Patients of SKYSONA and Natural History Populations

Isolated Pyramidal Tract Disease

Two untreated patients in Study 3 had early CALD with isolated pyramidal tract disease on brain MRI. Both remained asymptomatic for approximately 10 years following CALD diagnosis with first symptoms documented at 19 and 20 years of age. Ten patients with early, active pyramidal tract disease were treated with SKYSONA in Studies 1 and 2, and have only been followed a maximum of 77 months following treatment and to a maximum age at last follow-up of 15 years. Two (20%) SKYSONA-treated patients were diagnosed with myelodysplastic syndrome (MDS) and received allo-HSCT as treatment of the hematologic malignancy. One (10%) patient developed symptoms and worsening lesions on brain MRI approximately 6 months following treatment with SKYSONA and was withdrawn from the study to receive allo-HSCT at the investigator's discretion. He subsequently died of transplant-related causes.

Comparison of SKYSONA with Allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT)

There were insufficient data to compare relative efficacy of SKYSONA to the standard of care, allogeneic hematopoietic stem cell transplant (allo-HSCT) in the treatment of CALD. However, while it does not inform the efficacy analysis, comparison of SKYSONA with an external allo-HSCT control (pooled from Study 3 and from a mixed prospective and retrospective allo-HSCT data collection study, Study 4) was performed for overall survival (OS) due to concerns about treatment-related toxicities. OS was analyzed as time-to-event Kaplan-Meier estimates comparing SKYSONA (entire efficacy population, N=61) to early, active allo-HSCT subpopulations by donor type: human leukocyte antigen (HLA)-Matched allo-HSCT Subpopulation (N=34) and HLA-Mismatched allo-HSCT Subpopulation (N=17) (Figure 2). There were insufficient long-term data to compare OS beyond Month 24. However, a distinct difference in OS in the first 9 months following treatment was seen for the subpopulation who received allo-HSCT from an HLA-mismatched donor as compared to SKYSONA and allo-HSCT from an HLA-matched donor. While this analysis does not provide evidence of efficacy of SKYSONA, it does demonstrate a survival advantage of SKYSONA as compared to allo-HSCT from an HLA-mismatched donor, with early mortality in the HLA-mismatched allo-HSCT Subpopulation largely attributed to allo-HSCT-related toxicities.

No patient experienced acute (≥ Grade II) or chronic graft versus host disease (GVHD) after SKYSONA treatment.

Figure 2 Kaplan-Meier Curve of Overall Survival Between SKYSONA and Allo-HSCT Treated Populations

Post-treatment Brain MRI

At Month 24 following treatment with SKYSONA, 7/36 (19%) evaluable patients had a cerebral MRI Loes score increase of ≥ 6 points; 3/30 (10%) evaluable allo-HSCT patients had a cerebral MRI Loes score increase of ≥ 6 points.

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

• Store SKYSONA frozen in the vapor phase of liquid nitrogen at less than or equal to -140°C (-220°F) until ready for thaw and administration.
• Thaw SKYSONA prior to infusion [see Dosage and Administration (2) ].
• Do not re-freeze after thawing.
• Do not irradiate SKYSONA as this could lead to inactivation.