SKYSONA™ RESOURCES FOR YOU AND YOUR PATIENTS

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.

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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

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 based on available treatment options since their clinical symptoms do not usually occur until adulthood.

In two 24-month, open-label, single-arm studies in patients with early, active CALD, estimated MFD-free survival at Month 24 from time of symptom onset (first NFS≥1) was 72% (95% CI: 35%, 90%) for the symptomatic SKYSONA-treated patients (n=11) and 43% (95% CI: 10%, 73%) for the untreated patients (n=7; Natural History Population).*^†

*Based on post hoc enrichment analysis in symptomatic patients that compared time from onset of symptoms (NFS≥1) to time to first MFD or death (ie, MFD-free survival) in SKYSONA treated and untreated natural history controls whose data derived from existing medical records for patients with CALD.

^†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).

MFD = major functional disability; NFS = neurologic function score.

For the first 15 years after treatment with SKYSONA, patients should be monitored 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 once annually. Participants in the 15-year registry will be monitored for the duration of the registry, but all patients are required to be monitored. Patients are encouraged to enroll in the 15-year registry study post treatment. There will also still need to be continued monitoring and managing of your patient's cerebral adrenoleukodystrophy (ALD). How should patients treated with SKYSONA be monitored for hematologic malignancy?

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 7.5 years after SKYSONA administration. Malignancies are life-threatening and death related to treatment for malignancy has occurred.

SKYSONA Lenti-D lentiviral vector integration into proto-oncogenes, including MECOM, appears to have mediated the cases of hematologic malignancy. 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 including allogeneic hematopoietic stem cell transplant for patients who have a suitable, willing, and available matched sibling donor, prior to the decision to treat a child with SKYSONA.

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 × 10⁹/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 bluebird bio at 1-833-999-6378 for reporting and to obtain instructions on collection of samples for further testing.

Most common non-laboratory adverse reactions (≥20%): mucositis, nausea, vomiting, febrile neutropenia, alopecia, decreased appetite, abdominal pain, constipation, pyrexia, diarrhea, headache, rash.

Most common Grade 3 or 4 laboratory abnormalities (≥40%): leukopenia, lymphopenia, thrombocytopenia, neutropenia, anemia, hypokalemia.

If you have a potential patient who may benefit from SKYSONA treatment, please contact my bluebird support at 1-833-888-NEST (6378), or you can contact a bluebird bio Qualified Treatment Center (QTC) for referral assistance.