Skysona

Skysona must be administered in a qualified treatment centre by a physician(s) with experience in HSC transplantation and in the treatment of patients with neurological disorders. Posology Treatment consists of a single dose for infusion containing a dispersion of CD34+ cells in one or more infusion bags.

The minimum recommended dose of Skysona is 5 × 106 CD34+ cells/kg. 2 × 106 CD34+ cells/kg have been administered. 1 for description of the mobilisation regimen used in clinical studies). The patient's weight at first apheresis collection should be used to calculate the final dose.

The minimum target number of CD34+ cells to be collected is 12 × 106 CD34+ cells/kg. If the minimum dose of Skysona 5 × 106 CD34+ cells/kg is not met after initial medicinal product manufacturing, the patient may undergo one or more additional cycles of mobilisation and apheresis, separated by at least 14 days, in order to obtain more cells for additional manufacture.

5 × 106 CD34+ cells/kg is required. These cells must be collected from the patient and be cryopreserved prior to initiating conditioning and infusion with Skysona. 4). 4). 1 for a description of the conditioning regimens used in clinical studies).

6 for details on Skysona administration and handling. After Skysona administration Any blood products required within the first 3 months after Skysona infusion should be irradiated. Special populations Previous gene therapy administration Skysona has not been studied in patients previously treated with a gene therapy medicinal product.

There is no experience treating a patient more than once with Skysona. Renal impairment Skysona has not been studied in patients with renal impairment. Patients should be assessed for renal impairment to ensure Skysona therapy is appropriate.

No dose adjustment is required. Hepatic impairment Skysona has not been studied in patients with hepatic impairment. Patients should be assessed for hepatic impairment to ensure Skysona therapy is appropriate. No dose adjustment is required.

Female patients The safety and efficacy of Skysona in female patients have not been established. No data are available. Paediatric population The safety and efficacy of Skysona in children aged up to 3 years have not been established.

1). 9%). Given the small patient population and size of cohorts, adverse reactions in the table below do not provide a complete perspective on the nature and frequency of these events. 1. Tabulated list of adverse reactions Adverse reactions are listed by MedDRA body system organ class and by frequency.

Frequencies are defined as: very common (≥1/10) and common (≥1/100 and <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Tables 1, 2, and 3 are lists of adverse reactions attributed to mobilisation/apheresis, conditioning, and Skysona, respectively, experienced by patients with CALD in clinical studies with Skysona.

Table 1 Adverse reactions attributed to mobilisation/apheresis System Organ Class (SOC) Very common Common Blood and lymphatic system disorders Thrombocytopenia, Anaemia Metabolism and nutrition disorders Hypokalaemia Hypomagnesaemia Nervous system disorders Headache Vascular disorders Hypertension Gastrointestinal disorders Vomiting, Nausea, Paraesthesia oral Skin and subcutaneous tissue disorders PruritusMedicinal product no longer authorised 9 Musculoskeletal and connective tissue disorders Bone pain, Pain in extremity, Investigations Haemoglobin decreased Table 2 Adverse reactions attributed to conditioning System Organ Class (SOC) Very common Common Infections and infestations Pseudomonal bacteraemia, Bacteraemia, Streptococcal bacteraemia, Pneumonia, Bacterial infection, Device related infection, Enterocolitis infectious, Gastroenteritis viral, Oral candidiasis, Otitis media, Pharyngitis streptococcal, Respiratory syncytial virus infection, Rhinovirus infection, Sinusitis, Skin infection, Upper respiratory tract infection bacterial, Viral upper respiratory tract infection, Folliculitis, Anal candidiasis Blood and lymphatic system disorders Febrile neutropenia, Neutropenia, Thrombocytopenia, Anaemia, Leukopenia, Lymphopenia Lymph node pain Endocrine disorders Adrenal insufficiency, Inappropriate antidiuretic hormone secretion Metabolism and nutrition disorders Hypokalaemia, Hypomagnesaemia, Decreased appetite, Hypophosphataemia Hypoglycaemia, Fluid retention, Hyponatraemia Psychiatric disorders Aversion, Insomnia Nervous system disorders Headache Sensory loss, Tremor, Hyporeflexia Eye disorders Conjunctival haemorrhage Cardiac disorders Bradycardia, Sinus tachycardia, Tachycardia Vascular disorders Hypertension Petechiae Respiratory, thoracic and mediastinal disorders Epistaxis Hypoxia, Tachypnoea, Cough, Oropharyngeal pain, Rhinorrhoea Gastrointestinal disorders Stomatitis, Vomiting, Diarrhoea, Abdominal pain, Constipation, Nausea Gastritis, Gastrointestinal inflammation, Anal fissure, Proctitis, Anal pruritis, Dyspepsia, Oral pain, Proctalgia Skin and subcutaneous tissue disorders Alopecia, Skin hyperpigmentation Rash pustular, Skin exfoliation, Dermatitis diaper, Drug eruption, Dry skin,Medicinal product no longer authorised 10 Hyperhidrosis, Pruritis, Rash, Rash maculo-papular Renal and urinary disorders Haematuria, Incontinence, Urinary incontinence, Dysuria, Urinary tract pain Reproductive system and breast disorders Penile pain, Scrotal ulcer General disorders and administration site conditions Pyrexia Face oedema, Mucosal inflammation, Fatigue Investigations Alanine aminotransferase increased, Aspartate aminotransferase increased Occult blood positive, Adenovirus test positive, International normalised ratio increased, Blood alkaline phosphatase increased, Blood immunoglobulin G decreased, Blood lactate dehydrogenase increased, C-reactive protein increased, Weight decreased, Weight increased Injury, poisoning and procedural complications Allergic transfusion reaction, Table 3 Adverse reactions attributed to Skysona System Organ Class (SOC) Very common Common Infections and infestations Cystitis viral Blood and lymphatic system disorders Pancytopenia Gastrointestinal disorders Vomiting Description of selected adverse reactions Haematopoietic reconstitution Two serious reactions of pancytopenia occurred in two patients, with onset following neutrophil engraftment.

Traceability The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient should be kept for a period of 30 years after expiry date of the product.

Autologous use Skysona is intended solely for autologous use and should under no circumstances be administered to other patients. Skysona must not be infused if the information on the patient-specific label on the infusion bag(s), Lot Information Sheet and metal cassette(s) do not match the intended patient.

Mobilisation and myeloablative conditioning medicinal products Warnings and precautions of the mobilisation agents and the conditioning agents must be considered. Hypersensitivity reactions The dimethyl sulfoxide (DMSO) in Skysona may cause severe hypersensitivity reactions, including anaphylaxis.

Engraftment failure as measured by neutrophil engraftment Treatment with Skysona involves the infusion and engraftment of CD34+ HSCs that have been genetically modified ex vivo with a Lentiviral vector (LVV). 1). 2). Prolonged cytopenias Patients may exhibit cytopenias for several months following conditioning and Skysona infusion and cases of pancytopenia have been reported.

In clinical studies with Skysona, Grade 3 or higher cytopenias after Day 60 following infusion occurred in 26% of patients and included decreased platelet count (13%), decreased neutrophil count (17%), and decreased hemoglobin (2%).

After 100 days following infusion, 16% of patients had any Grade 3 or higher cytopenia, including decreased platelet count (9%), decreasedMedicinal product no longer authorised 6 neutrophil count (11%); no patient had Grade 3 or higher decreased haemoglobin (0%).

Blood counts should be monitored after Skysona infusion and patients should be evaluated for signs and symptoms of bleeding and infection. Risk of insertional oncogenesis There are no reports of LVV-mediated insertional mutagenesis resulting in oncogenesis, including myelodysplasia, leukaemia, or lymphoma, associated with Skysona.

1. Contraindications to the mobilisation agents and the conditioning agents must be considered.