Skysona - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Skysona 2–30 × 106 cells/mL dispersion for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION2.1 General description

Skysona (elivaldogene autotemcel) is a genetically modified autologous CD34+ cell-enriched population that contains haematopoietic stem cells (HSCs) transduced ex vivo with lentiviral vector (LVV) encoding ABCD1 complementary deoxyribonucleic acid (cDNA) for human adrenoleukodys­trophy protein (ALDP).

2.2 Qualitative and quantitative composition

Each patient-specific infusion bag of Skysona contains elivaldogene autotemcel at a batch-dependent concentration of genetically modified autologous CD34+ cell enriched population. The finished product is packaged in one or more infusion bags, containing a dispersion of 2–30 × 106 cells/mL of CD34+ enriched cell population suspended in cryopreservative solution. Each infusion bag contains approximately 20 mL of dispersion for infusion.

The quantitative information of medicinal product regarding strength, CD34+ cells, and dose for the specific patient is provided in the Lot Information Sheet. The Lot Information Sheet is included inside the lid of the cryoshipper used to transport Skysona.

Excipient(s) with known effect

Each dose contains 391–1564 mg sodium (included in Cryostor CS5).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Dispersion for infusion.

A colourless to white to red, including shades of white or pink, light yellow, and orange dispersion.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Skysona is indicated for the treatment of early cerebral adrenoleukodys­trophy in patients less than 18 years of age, with an ABCD1 genetic mutation, and for whom a human leukocyte antigen (HLA)-matched sibling haematopoietic stem cell (HSC) donor is not available (see section 5.1).

4.2 Posology and method of administration

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. In clinical studies doses up to 38.2 × 106 CD34+ cells/kg have been administered.

Mobilisation and apheresis

Patients are required to undergo HSC mobilisation followed by apheresis to obtain CD34+ stem cells which will be used for medicinal product manufacturing (see section 5.1 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.

A back-up collection of CD34+ stem cells of > 1.5 × 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. The back-up collection may be needed for rescue treatment if there is: 1) compromise of Skysona after initiation of conditioning and before Skysona infusion, 2) primary engraftment failure, or 3) loss of engraftment after infusion with Skysona (see section 4.4).

Pre-treatment conditioning

The treating physician should confirm that Skysona therapy is appropriate for the patient before conditioning is initiated (see section 4.4).

Myeloablative conditioning must be administered before infusion of Skysona (see section 5.1 for a description of the conditioning regimens used in clinical studies).

Conditioning should not begin until the complete set of infusion bag(s) constituting the dose of Skysona has been received at the administration site, and the availability of the back-up collection is confirmed.

Skysona administration

See Method of Administration below and section 6.6 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. No data are available.

Patients seropositive for human immunodeficiency virus (HIV)

Skysona has not been studied in patients with HIV-1, HIV-2, HTLV-1, and 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.

Method of administration

Skysona is for intravenous use only.

For detailed instructions on preparation, administration, accidental exposure and disposal of Skysona, see section 6.6.

After completion of the conditioning, there must be a minimum of 48 hours of washout before Skysona infusion.

Before infusion, it must be confirmed that the patient’s identity matches the unique patient information on the Skysona infusion bag(s). The total number of infusion bags to be administered should also be confirmed with the Lot Information Sheet (see section 4.4).

Skysona infusion should be completed as soon as possible and no more than 4 hours after thawing. Each infusion bag should be administered in less than 60 minutes. In the event that more than one infusion bag is provided, all infusion bags must be administered consecutively. The entire volume of each infusion bag should be infused.

Standard procedures for patient management in line with HSC transplantation should be followed after Skysona infusion.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

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

4.4 Special warnings and precautions for use

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). Failure of neutrophil engraftment is a short-term but potentially severe risk, defined as failure to achieve 3 consecutive absolute neutrophil counts (ANC) > 500 cells/^L obtained on different days by Day 43 after infusion of Skysona (see section 5.1). Patients who experience neutrophil engraftment failure should receive rescue treatment with the back-up collection (see section 4.2).

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%), decreased 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. Nevertheless, there is a theoretical risk after treatment with Skysona. Clonal expansion resulting in clonal predominance without clinical evidence of malignancy has been detected in some patients treated with Skysona.

Patients should be monitored at least annually for myelodysplasia, leukaemia, or lymphoma (including with a complete blood count) for 15 years post treatment with Skysona. If myelodysplasia, leukaemia, or lymphoma is detected in a patient who received Skysona, blood samples should be collected for integration site analysis.

Serological testing

All patients should be tested for HIV-1/-2 prior to mobilisation and apheresis to ensure acceptance of the apheresis material for Skysona manufacturing (see section 4.2).

Anti-retroviral use

Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation (see section 4.5). If a patient requires anti-retrovirals for HIV prophylaxis, Skysona treatment, including mobilisation and apheresis of CD34+ cells through Skysona infusion, should be delayed until an HIV infection could be adequately ruled out according to local guidance for HIV testing.

Interference with serology testing

It is important to note that patients who have received Skysona are likely to test positive by polymerase chain reaction (PCR) assays for HIV due to LVV provirus insertion, resulting in a false positive test for HIV. Therefore, patients who have received Skysona should not be screened for HIV infection using a PCR-based assay.

Blood, organ, tissue and cell donation

Patients treated with Skysona should not donate blood, organs, tissues, or cells for transplantation at any time in the future. This information is provided in the Patient Information Leaflet and also in the Patient Alert Card which must be given to the patient.

After Skysona administration

There are no data showing an effect of Skysona treatment on the adrenal insufficiency related to ALD. Replacement therapy should be continued.

Patients are expected to enrol in a registry-based study and will be followed in the registry in order to better understand the long-term safety and efficacy of Skysona.

Sodium content

This medicinal product contains 391–1564 mg sodium per dose, equivalent to 20–78% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

Patients should not take anti-retroviral medicinal products from at least one month prior to mobilisation until at least apheresis is completed (see section 4.4).

No formal drug interaction studies have been performed. Skysona is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters.

Live vaccines

The safety of immunisation with live viral vaccines during or following Skysona treatment has not been studied. Vaccination with live virus vaccines is not recommended during the 6 weeks preceding the start of myeloablative conditioning, and until haematological recovery following treatment with Skysona.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Con­traception in males and females

There are insufficient exposure data to provide a precise recommendation on duration of contraception following treatment with Skysona. Women of childbearing potential and men capable of fathering a child and their female partners must use an effective method of contraception (intrauterine device or combination of hormonal and barrier contraception) from start of mobilisation through at least 6 months after administration of Skysona. The SmPC of the conditioning agents should be consulted for information on the need for effective contraception in patients who undergo conditioning.

A negative serum pregnancy test in women of childbearing potential must be confirmed prior to the start of mobilisation and re-confirmed prior to conditioning procedures and before medicinal product administration.

Pregnancy

No clinical data on exposed pregnancies are available.

Reproductive and developmental toxicity studies with Skysona were not performed. Skysona must not be used during pregnancy because of conditioning (see section 4.3). It is unknown whether Skysona transduced cells have the potential to be transferred in utero to a foetus. Pregnancy after treatment with Skysona should be discussed with the treating physician.

There is no opportunity for germline transmission of the LVV that encodes an ABCD1 cDNA for human ALDP after treatment with Skysona, therefore the likelihood that an offspring would have general somatic expression of the lentiviral vector that encodes an ABCD1 cDNA for human ALDP is considered negligible.

Breast-feeding

It is unknown whether Skysona is excreted in human milk. The effect of administration of Skysona to mothers on their breast-fed children has not been studied.

Skysona must not be administered to women who are breast-feeding.

Fertility

There are no data on the effects of Skysona on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

Data are available on the risk of infertility with conditioning. It is therefore advised to consider cryopreservation of semen or ova before treatment.

4.7 Effects on ability to drive and use machines

Skysona has no influence on the ability to drive or use machines.

The effect of the mobilisation agents and the conditioning agents on the ability to drive or use machines, or engage in activities such as cycling or skateboarding, must be considered.

4.8 Undesirable effects

Summary of the safety profile

The safety of Skysona was evaluated in 51 patients with CALD in Studies ALD-102, ALD-104, and LTF-304 (see section 5.1). The most serious adverse reaction attributed to Skysona was pancytopenia (3.9%). 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. Information related to safety endpoints used in the studies is provided in section 5.1.

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		Pruritus

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,

		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. Both patients had delayed hematopoietic reconstitution requiring prolonged support with blood and platelet transfusions as well as growth factors (G-CSF and eltrombopag). One patient had intercurrent parvovirus. Both events were ongoing at least 18 months after Skysona infusion.

Infusion-related reactions

Vomiting occurred in two patients on the day of infusion, potentially related to the cryopreservation agent. Premedication may be utilized at physician discretion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

No data from clinical studies are available regarding overdose of Skysona.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other nervous system drugs, ATC code: not yet assigned

Mechanism of action

Skysona adds functional copies of the ABCD1 cDNA into patients’ 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+) that migrate to the brain where they are believed to further differentiate into macrophages and cerebral microglia that can produce functional ALDP. The functional ALDP can then enable the local degradation of very long chain fatty acids (VLCFAs) in the brain, which in turn can stabilise the disease by preventing further inflammation and demyelination. However, it is not anticipated that Skysona treatment will affect other manifestations of ALD including adrenal insufficiency. Impact of Skysona treatment on adrenomyelone­uropathy has not been studied. Following successful engraftment with genetically modified cells, the expression of ALDP is expected to be life-long.

Pharmacodynamic effects

One month after Skysona treatment, all evaluable patients in Study ALD-102 (N = 25) produced ALDP in CD14+ peripheral blood cells with a median (min, max) CD14+ ALDP+ of 29.50% (8.20%, 49.65%) demonstrating early expression of the transgene. For patients with at least 6 months of follow-up, CD14+ ALDP+ cells generally declined slightly after Skysona infusion and stabilized by approximately Month 6. Patients had a Month 6 median (min, max) CD14+ %ALDP+ of 22.20% (2.00%, 71.40%) in Study ALD-102 (N = 27).

The percentage of ALDP+ cells remained generally stable in CD14+ peripheral blood cells through Month 24 with a median (min, max) of 16.90% (5.80%, 44.60%) in Study ALD-102 (N = 26). The percentage of CD14+ ALDP+ cells continued to be stable at last follow-up through Month 60, demonstrating long-term expression of transgenic ALDP in the progeny of haematopoietic stem cells.

Clinical efficacy and safety

The safety and efficacy of Skysona were assessed in an open-label, single-arm study in patients with CALD (ALD-102; N = 32) and compared to the efficacy and safety of allo-HSCT in patients with CALD in a contemporaneous comparator study (ALD-103; N = 59). All patients who completed or discontinued Study ALD-102 were asked to participate in a long-term follow-up study, LTF-304.

Enrolment in Study ALD-102 is complete with 32 patients enrolled and treated; 30 patients are evaluable for the Month 24 primary efficacy endpoint.

In addition, a second open-label, single-arm study (ALD-104; N = 19) is ongoing; no patients have reached the Month 24 evaluation timepoint and thus are not included in any efficacy analyses.

Mobilisation and apheresis

All patients were administered a median dose of 10 ^g/kg of G-CSF for a minimum of 4 days to mobilise stem cells prior to the apheresis procedure.

In Study ALD-102, patients were assessed on the morning after the 4th G-CSF dose. If the peripheral blood CD34+ count on that morning was <50 cells/^L, a 5th dose of G-CSF was administered and plerixafor was administered at a dose of 0.24 mg/kg of body weight approximately 10 hours prior to the next day’s apheresis collection. Plerixafor could be given daily for up to 4 days. Eleven of the 32 (34.4%) patients in Study ALD-102 received plerixafor.

For all patients, 1 cycle of mobilisation and apheresis was sufficient to collect the minimum number of CD34+ cells to manufacture Skysona.

Pre-treatment conditioning

In Study ALD-102, 32 patients received pharmacokinetically-dosed busulfan in conjunction with cyclophosphamide prior to treatment with Skysona. Busulfan was administered with a recommended cumulative AUC of 17,000 to 21,000 |jmol*min/L over four days of conditioning. For patients < 12 kg, busulfan was dosed at 1.1 mg/kg/dose IV every 6 hours and for patients > 12 kg busulfan was dosed at 0.8 mg/kg/dose IV every 6 hours for 4 days. Busulfan dose adjustments were made as needed based on pharmacokinetic monitoring. Patients received anti-seizure, anti-fungal, and antibiotic prophylaxis in accordance with institutional guidelines. The recommended dose of cyclophosphami­de was

50 mg/kg/day. The median (min, max) daily average busulfan dose was 3.5 (2.8, 4.2) mg/kg/day (N = 31) and the median (min, max) estimated average daily AUC was 4729 (4039, 5041) ^mol*min/L/dav (N = 31).

In Study ALD-104, 19 patients received pharmacokinetically-dosed busulfan in conjunction with fludarabine prior to treatment with Skysona.

Skysona administration

All patients were administered Skysona as an intravenous infusion with a median (min, max) dose of 11.78 (5.0, 38.2) x 106 CD34+ cells/kg (N = 51).

After Skysona administration

In Study ALD-102, patients received G-CSF at the investigator’s dis­cretion per institutional practice following treatment with Skysona. Of the 32 treated patients, 24 received G-CSF following treatment with Skysona.

In Study ALD-104, patients were to receive G-CSF beginning on Day 5 following treatment with Skysona.

Study ALD-102

Study ALD-102 was an open-label, single-arm, 24-month study that included a total of 32 patients with CALD treated with Skysona. In study ALD-102, early CALD was defined as: a Loes score between 0.5 and 9 (inclusive), gadolinium enhancement on MRI of demyelinating lesions and a neurologic function score (NFS) of < 1, indicating limited changes in neurologic function. Patients were excluded from Study ALD-102 if they had a willing and available HLA-matched sibling HSC donor. The median (min, max) age at Skysona infusion was 6.0 (4, 14) years, 100% of patients were males, and 46.9% were White/Caucasian. The median (min, max) Loes score at baseline was 2.00 (1.0, 9.0). Of the 32 patients, 31 had an NFS of 0 and one had an NFS of 1 at baseline. All patients that completed ALD-102 enrolled for long-term follow-up in the LTF-304 study. The median (min, max) duration of follow-up was 38.59 (13.4, 82.7) months.

The primary efficacy endpoint was the proportion of patients who had none of the 6 Major Functional Disabilities (MFDs), were alive, did not receive a second allo-HSCT or rescue cell administration, and had not withdrawn or been lost to follow-up at Month 24 (i.e., Month 24 MFD-free survival). The 6 MFDs are: loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, or complete loss of voluntary movement.

An analysis was conducted after 30 patients were evaluable for the primary efficacy endpoint, Month 24 MFD-free survival. Twenty-seven out of 30 patients (90%, 95% CI: 73.5, 97.9) achieved Month 24 MFD-free survival, with the lower bound of 95% CI above the clinically meaningful benchmark (Month 24 MFD-free survival rate of 50%) indicating that treatment with Skysona provides clinically meaningful benefits by preserving motor function and communication ability and improves survival when compared to untreated patients at an early stage of cerebral disease.

A contemporaneous comparator study was conducted in 59 patients with CALD treated with allo-HSCT (ALD-103 Safety Population). A subset of 27 patients (ALD-103 Efficacy Population) was matched to the ALD-102 population for baseline Loes score, presence of contrast enhancement and NFS score. This population was further divided into those who received an allo-HSCT from a matched sibling donor (N = 10; ALD-103 Efficacy Population with MSD) and those who received an allo-HSCT from an alternative donor source, i.e., not a matched sibling donor (N = 17; ALD-103 Efficacy Population without MSD).

MFD-free survival over time and overall survival were analysed in 32 patients in ALD-102 and compared to 17 patients treated with allo-HSCT in the ALD-103 Efficacy Population (without MSD), which are presented in Table 4 and Figure 1.

Skysona showed a durable effect on MFD-free survival, with most patients (26/27, 96.3%) that enrolled in LTF-304 remaining alive and maintaining their MFD-free status through their last follow-up on study, including 14 patients with 5 or more years of follow-up. One patient refused further follow-up.

Table 4: Efficacy Endpoints

	ALD-102 Skysona Treateda (N=32)	ALD-103 Allo-HSCT Efficacy Populationb (N=27)	ALD-103 Allo-HSCT Efficacy Population6 without MSD (N=17)	ALD-103 Allo-HSCT Efficacy Populationd with MSD (N=10)
Proportion of MFD-Free Survival6 at Month 24
Evaluable Patientsf	30	18	9	9
n	27	14	6	8
%	90.0%	77.8%	66.7%	88.9%
[95% CI]	[73.5, 97.9]	[52.4, 93.6]	[29.9, 92.5]	[51.8, 99.7]
Number of Patients with Events by Month 24g
n	3	8	6	2
%	9.4%	29.6%	35.3%	20.0%
Number of Surviving Patients by Month		24h
n	31	22	14	8
%	96.6%	86.2%	86.3%	88.9%
[95% CI]	[77.9, 99.5]	[62.6, 95.4]	[54.7, 96.5]	[43.3, 98.4]

aentry criteria included elevated VLCFA values, a Loes score between 0.5 and 9 (inclusive), gadolinium enhancement on MRI of demyelinating lesions, NFS of < 1 and no willing and available HLA-matched sibling HSC donor

bmatched to the ALD-102 population for baseline Loes score, presence of contrast enhancement, and NFS score

cmatched to the ALD-102 population for baseline Loes score, presence of contrast enhancement, and NFS score and no willing and available HLA-matched sibling HSC donor

dmatched to the ALD-102 population for baseline Loes score, presence of contrast enhancement, and NFS score and had an HLA-matched sibling HSC donor

ePrimary efficacy endpoint; proportion of patients with no event by Month 24; includes death, MFD, rescue cell administration, or subsequent allo-HSCT

fALD-102 and ALD-103 Month 24 Evaluable Subjects for MFD-free Survival are defined as treated subjects who had been followed for 24 months, or had completed the Month 24 Visit, or had discontinued from the studies (for any reason, including death) but would have been followed for 24 months if still in the study, at the time of the data cut for these analyses

gTime-to-event Kaplan-Meier analysis; includes death, MFD, rescue cell administration, or subsequent allo-HSCT

hTime-to-event Kaplan-Meier analysis; includes death only

MSD = matched sibling donor.

Kaplan-Meier Curve of MFD-free Survival Between ALD-102 (Skysona Treated) and ALD-103 Efficacy Population (without MSD and with MSD)

The neurologic function score (NFS) was used as a secondary endpoint to evaluate 15 domains of neurological function; it has a total maximum score of 25. A score of 0 denotes no abnormality in the assessed areas of neurological function. At baseline, patients were required to have an NFS < 1. In ALD-102, 26 of 28 evaluable patients maintained an NFS less than or equal to 1 through Month 24 and 24 of those patients had no change in their NFS, which showed maintenance of neurological function in the majority of patients. The majority of patients in ALD-102 maintained cognitive function (IQ, including performance IQ sub-measures) within the normal range (100 ± 15 points), with minimal decline and with stabilization by Month 24. A small subgroup of patients who had higher Loes scores at baseline tended to have a less favourable outcome.

The primary safety endpoint, the proportion of evaluable patients who experienced either acute (> Grade II) or chronic graft versus host disease (GVHD) in ALD-102 vs. ALD-103 by Month 24, was 0 vs. 52%.

The proportion of all patients who experienced either acute (> Grade II) or chronic GVHD in ALD-102/ALD-104 vs. ALD-103 is summarized in Table 5.

Table 5: Graft Versus Host Disease

	Skysona treated		Allo-HSCT
	ALD-102 (N = 32)	ALD-102/104 (N = 51)	ALD-103 Safety Population3 (N = 59)
Acute (> Grade II) GVHD or Chronic GVHD
n	0	0	26
%	0%	0%	44.1%
[95% CI]	[0.0, 10.9]	[0.0, 7.0]	[31.2, 57.6]
Acute (> Grade II) GVHD
n	0	0	15
%	0%	0%	25.4%
[95% CI]	[0, 10.9]	[0.0, 7.0]	[15.0, 38.4]
Chronic GVHD
n	0	0	14
%	0%	0%	23.7%
[95% CI]	[0, 10.9]	[0.0, 7.0]	[13.6, 36.6]

aFor censored observations in the ALD-103 Safety Population, it was assumed that no GVHD was observed in any category

Neutrophil engraftment was monitored as a secondary endpoint and was defined as achieving 3 consecutive absolute neutrophil counts (ANC) > 500 cells/^L obtained on different days by Day 43 after Skysona infusion. In clinical studies neutrophil engraftment occurred on median (min, max) Day 13 (11, 41) after Skysona infusion (see section 4.4) (N = 32, ALD-102; N = 17, ALD-104) compared to Day 17 (12, 36) in ALD-103 (N = 53).

No primary or secondary neutrophil engraftment failure was observed in subjects in ALD-102/ALD-104 (N=51), compared to 10/59 (16.9%) subjects in ALD-103.

Platelet engraftment was monitored as a secondary endpoint and was defined as achieving 3 consecutive unsupported platelet counts of > 20 × 109 cells/L obtained on different days after Skysona infusion, with no platelet transfusions administered for 7 days immediately preceding and during the evaluation period. In clinical studies, platelet engraftment occurred on median (min, max) Day 32 (14, 108) after Skysona infusion (N = 32, ALD-102; N = 15, ALD-104) compared to Day 26 (13, 67) in ALD-103 (N = 47).

No patients experienced transplant-related mortality (TRM), a secondary endpoint, at 100 days or 365 days after transplant in ALD-102 and ALD-104. In contrast, 2/59 (3.4%) patients experienced TRM at 100 days and 8/59 (13.6%) patients experienced TRM at 365 days after transplant in the ALD-103 Safety Population.

5.2 Pharmacokinetic properties

Skysona is an autologous gene therapy medicinal product consisting of autologous cells 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.

5.3 Preclinical safety data

Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted.

The pharmacology, toxicology and genotoxicity of the Lenti-D LVV used for transduction were evaluated in vitro and in vivo. In an in vitro immortalization assay, Lenti-D LVV-transduced mouse bone marrow cells showed strongly reduced mutagenic potential as compared to positive control vectors. Integration site analysis of pre-transplantation Lenti-D LVV-transduced human CD34+ HSCs demonstrated the expected self-inactivating LVV integration profile, with no enrichment for insertion in or near cancer-related genes.

A pivotal GLP-compliant combined toxicity, genotoxicity and biodistribution study of Lenti-D LVV-transduced mobilized peripheral blood CD34+ HSCs was conducted in myeloablated immunodeficient mice. There was no evidence of toxicity, genotoxicity (insertional mutagenesis resulting in oncogenic mutations) or oncogenesis (tumorigenicity) related to Lenti-D LVV integration. Integration site analysis of post-transplantation bone marrow cells demonstrated no preferred integration in the proximity of or within cancer-related genes. An additional study with Lenti-D LVV-transduced human CD34+ HSCs administered to myeloablated, immunodeficient mice demonstrated engraftment of humanorigin microglial cells within brain tissues with no toxicity or tumorigenicity.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Cryostor CS5

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

6 months

Once thawed: maximum 4 hours at room temperature (20 °C – 25 °C)

6.4 Special precautions for storage

Store in the vapour phase of liquid nitrogen at < -140 °C until ready for thaw and administration.

Keep infusion bag(s) in the metal cassette(s).

Do not re-freeze after thawing.

For storage conditions after thawing of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Approximately 20 mL in a fluoro ethylenepropylene infusion bag(s), each packed in a transparent pouch inside a metal cassette.

Skysona is shipped from the manufacturing facility to the infusion centre storage facility in a cryoshipper, which may contain multiple metal cassettes intended for a single patient. Each metal cassette contains one infusion bag with Skysona. One lot of drug product may be packaged in either one or two 20 mL bags, depending on the total number of cells present. Multiple lots may be administered to the patient as a single dose.

6.6 Special precautions for disposal and other handling

Irradiation could lead to inactivation of the product.

Precautions to be taken before handling or administering the medicinal product

• • This medicinal product contains genetically modified human blood cells. Healthcare professionals handling Skysona should take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.
• • Keep the infusion bag(s) in the metal cassette(s) and store in the vapor phase of liquid nitrogen at < -140 °C until ready for thaw and administration.

Preparation for the infusion

• • Remove each metal cassette from liquid nitrogen storage and remove each infusion bag from the metal cassette.
• • Confirm that Skysona is printed on the infusion bag(s).
• • Confirm that patient identity matches the unique patient identification information located on the Skysona infusion bag(s) and on the Lot Information Sheet. Skysona is intended solely for autologous use. Do not infuse Skysona if the information on the patient-specific label on the infusion bag does not match the intended patient.
• • Ensure that you have the correct number of infusion bags and confirm each infusion bag is within the expiry date using the accompanying Lot Information Sheet.
• • Each infusion bag should be inspected for any breaches of integrity before thawing and infusion. If an infusion bag is compromised, follow the local guidelines for handling of waste of human-derived material and contact bluebird bio immediately.

Thawing

• • If more than one infusion bag is provided, thaw and administer each infusion bag completely before proceeding to thaw the next infusion bag.
• • Do not sample, alter, irradiate, or refreeze the medicinal product.
• • Thaw Skysona at 37 °C in a water bath or dry bath. Thawing of each infusion bag takes

approximately 2 to 4 minutes. Do not over thaw the medicinal product. Do not leave the medicinal product unattended and do not submerge the infusion ports in a water bath.

• • After thaw, mix the medicinal product gently by massaging the infusion bag until all of the contents are uniform.

Administration

• • Expose the sterile port on the infusion bag by tearing off the protective wrap covering the port.
• • Access the medicinal product infusion bag and infuse per the administration site’s standard

procedures for administration of cell therapy products. Do not use an in-line blood filter or an infusion pump.

• • Infuse Skysona as soon as possible and store for no more than 4 hours at room temperature (20 °C – 25 °C) after thawing.
• • Administer each infusion bag of Skysona via intravenous infusion over a period of less than

60 minutes.

• • Flush all Skysona remaining in the infusion bag and any associated tubing with at least 50 mL of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure as many cells as possible are infused into the patient.

7. MARKETING AUTHORISATION HOLDER

bluebird bio (Netherlands) B.V.

Stadsplateau 7

WTC Utrecht

3521AZ Utrecht

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/21/1563/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: