Summary of medicine characteristics - STRIMVELIS 1-10 MILLION CELLS/ML DISPERSION FOR INFUSION
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1 NAME OF THE MEDICINAL PRODUCT
Strimvelis 1–10 million cells/ml dispersion for infusion.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
An autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase (ADA) cDNA sequence from human haematopoietic stem/progenitor (CD34+) cells.
Qualitative and quantitative composition
The finished product is composed of one or more ethylene vinyl acetate (EVA) bags which contain an autologous CD34+ enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence.
The quantitative information regarding CD34+ cells/kg and total cells in the product is presented in the labelling for each batch. The concentration is 1–10 million CD34+ cells/ml.
Excipient with known effect
This medicinal product contains 0.15 mmol sodium per ml (see section 4.4).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Dispersion for infusion.
A cloudy to clear, colourless to pink dispersion of cells.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Strimvelis is indicated for the treatment of patients with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID), for whom no suitable human leukocyte antigen (HLA)-matched related stem cell donor is available (see section 4.2 and section 4.4).
4.2 Posology and method of administration
Strimvelis must be administered in a specialist transplant centre, by a physician with previous experience in the treatment and management of patients with ADA-SCID and in the use of autologous CD34+ ex vivo gene therapy products. Strimvelis should only be administered after consultation with the patient and/or family. Patients are expected to enrol in a posttreatment registry and will be followed-up long term.
A CD34+ stem cell back-up containing at least 1 million CD34+ cells per kg is required. This should be harvested from the patient at least 3 weeks prior to treatment with Strimvelis. The stem cell back-up is collected for use as rescue treatment should there be a failure during product manufacture, transplant failure, or prolonged bone marrow aplasia after treatment with Strimvelis.
The patient must be able to donate adequate CD34+ cells to deliver the minimum 4 million purified CD34+ cells/kg, required for manufacture of Strimvelis.
Strimvelis is intended for autologous use only (see section 4.4).
Before infusion, it must be confirmed that the patient’s identity matches the essential unique patient information on the Strimvelis infusion bag(s) and/or container (see sections 4.4 and 6.6).
Pre-treatment conditioning
It is recommended that 0.5 mg/kg intravenous busulfan be administered every 6 hours on two consecutive days starting three days before administration of Strimvelis. The total busulfan dose is 4 mg/kg, divided into 8 doses of 0.5 mg/kg. Busulfan plasma levels should be measured after the first dose of each day by serial blood sampling using an appropriate method. If busulfan AUC exceeds 4000 nanograms/ml*h (974 |imol/L.minute), the dose should be appropriately reduced based on the AUC.
Premedication
It is recommended that an intravenous antihistamine be administered 15
30 minutes before the infusion of Strimvelis.
Posology
The recommended dose range of Strimvelis is between 2 and 20 million CD34+ cells/kg.
If the product contains less than 2 million CD34+ cells/kg, the treating physician should make a decision whether to proceed with administration, based on an individual benefit risk assessment. Treatment failure was observed in a patient treated in the clinical trials with <2 millions CD34+cell/kg.
Strimvelis should be administered once only.
Special populations
Elderly
Strimvelis is not intended for use in patients >65 years of age, and has not been studied in this age group.
Renal impairment
Strimvelis has not been studied in patients with renal impairment. No dose adjustment is expected to be required.
Hepatic impairment
Strimvelis has not been studied in patients with hepatic impairment. No dose adjustment is expected to be required.
Paediatric population
The safety and efficacy of Strimvelis in children less than six months of age or over 6 years 1 month has not been established (see section 4.4). No data are available.
Method of administration
Strimvelis is for intravenous infusion.
A transfusion administration set with filter should be used. Only filters intended for use with transfusion sets should be used to prevent inadvertent removal of cells from the product.
The infusion rate should not exceed 5 ml/kg/h. The period of administration is approximately 20 minutes (see section 6.6). Following administration, a saline filled 50 ml syringe should be used to flush the bag through.
Precautions to be taken before manipulating or administering the , product
This medicinal product contains genetically-modified cells. Local biosafety guidelines applicable for such products should be followed (see section 6.6).
Strimvelis is not tested for transmissible infectious agents. Healthcare professionals handling Strimvelis should therefore take appropriate precautions to avoid potential transmission of infectious diseases.
4.3 Contraindications
Hypersensitivity to the product or to any of the excipients listed in section 6.1.
Current or previous history of leukaemia or myelodysplasia.
Positive test for human immunodeficiency virus (HIV) or presence of any other transmissible infectious agent listed in the current EU Cell and Tissue Directive prior to bone marrow harvest.
History of previous gene therapy.
4.4 Special warnings and precautions for use
Strimvelis is intended solely for autologous use and should never be administered to any patient other than the original CD34+ cell donor.
In some cases the patient may be unable to receive Strimvelis because of manufacturing issues. After notification, the treating physician may need to modify the treatment program of the patient accordingly (i.e. terminating the busulfan conditioning and/or administration of the stem cell back up treatment if appropriate).
Stage two quality control results will only be available after the product has been infused. If clinically relevant quality issues, such as out of specification results, are identified after Strimvelis has been infused, the treating physician will be notified. The physician should monitor and/or treat the patient as appropriate.
Strimvelis should be used with caution in patients older than 6 years and
1 month and younger than 6 months as there are no data from clinical trials in these age ranges. Older patients are typically less able to donate high numbers of CD34+ cells which may mean that older patients cannot be treated.
Successful generation of T cells after Strimvelis is also likely to be affected by residual thymic function which can become impaired in older children. Use of Strimvelis in patients older than those previously studied should be carefully considered and reserved only for occasions where all other reasonable treatment options have been exhausted.
Patients who have previously tested positive for hepatitis C can be treated with Strimvelis, provided they demonstrate absence of ongoing infection using a nucleic acid test with a limit of quantification of <15 international units/ml. Negative test results are required on at least 3 sequential occasions over a period of at least 4 weeks, after completion of treatment for hepatitis C, with the final test conducted no more than 3 days prior to cell harvest.
Strimvelis should be used with caution in patients with hypersensitivity to aminoglycosides or bovine serum albumin.
No cases of leukaemia or myelodysplasia have been reported following treatment with Strimvelis. However, vector insertions into chromosomal regions previously associated with leukaemia in comparable trials of gene therapy in Wiskott Aldrich Syndrome, X-SCID and Chronic Granulomatous Disease have been documented. Retroviral insertion sites (RIS) have been detected adjacent to or within CCND2 and LMO2 and there is a potential risk of leukaemic transformation following treatment with Strimvelis. It is recommended that patients be monitored long term with at least annual visits for the first eleven years and then at 13 and 15 years post treatment with Strimvelis, to include a complete blood count with differential, biochemistry and thyroid stimulating hormone.
The long term effects and durability of response to Strimvelis on ADA-SCID are unknown (see section 5.1).
Patients should be closely monitored for the occurrence of severe and opportunistic infections, immune reconstitution parameters and the need for replacement intravenous immunoglobulin (IVIG); in case of lack of response, it is recommended to introduce other ADA-SCID treatments under the supervision of a physician.
There have been cases where treatment with Strimvelis has been unsuccessful. Some patients have had to resume long-term enzyme replacement therapy and/or receive a stem cell transplant (see section 5.1).
Non-immunological manifestations of ADA-SCID may not respond to Strimvelis.
No immunogenicity testing has been conducted with Strimvelis.
Patients can develop autoimmunity. 67% (12 of 18) of Strimvelis treated patients had either autoimmune antibodies or other manifestations (e.g. autoimmune thrombocytopenia, autoimmune aplastic anaemia, autoimmune hepatitis and Guillain-Barré syndrome) (see section 4.8).
Patients treated with Strimvelis should not donate blood, organs, tissues and cells for transplantation, at any time in the future. This information is provided in the Patient Alert Card.
T-lymphocyte (CD3+) and NK (CD56+) cell counts improved following treatment with Strimvelis. Median values at 3 years post gene therapy were below the normal range. Continued follow-up is recommended. Cases of skin papillomas, abnormal serum protein electrophoresis and one case each of lipofibroma, pulmonary mass and decreased T-cell V beta repertoire were reported. No evidence of causality to the product has been established.
Adverse events related to the use of central venous catheters (CVCs) have been reported (e.g., serious CVC infections and thrombosis in the device).
Patients should be closely monitored for potential catheter-related events.
Sodium content
This medicinal product contains 0.15 mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. Strimvelis is not expected to interact with the hepatic cytochrome P-450 family of enzymes or drug transporters.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
As Strimvelis will be administered following busulfan conditioning, patients of childbearing potential must use reliable barrier contraception during administration of Strimvelis and for at least 6 months afterwards.
Pregnancy
No clinical data on exposed pregnancies are available.
Reproductive and developmental toxicity studies were not performed.
Strimvelis should not be used during pregnancy.
Breast-feeding
It is unknown whether Strimvelis is excreted in human milk. The effect on breast-fed infants of administration of Strimvelis to their mothers has not been studied.
Strimvelis should not be administered to women who are breast-feeding.
Fertility
There are no data on the effects of Strimvelis on human fertility. Effects on male and female fertility have not been evaluated in animal studies.
4.7 Effects on ability to drive and use machines
Strimvelis has no or negligible long term influence on the ability to drive and use machines.
4.8 Undesirable effects
Summary of the safety profile
The safety of Strimvelis was evaluated in 18 subjects, with a median duration of follow-up of 12 years.
Given the small patient population and size of the cohorts, adverse reactions in the table do not provide a complete perspective on the nature and frequency of these events. Serious adverse reactions include autoimmunity (e.g. autoimmune haemolytic anaemia, autoimmune aplastic anaemia, autoimmune hepatitis, autoimmune thrombocytopenia and Guillain-Barre syndrome). The most commonly reported adverse reaction was pyrexia.
Tabulated list of adverse reactions
Adverse reactions are listed below by MedDRA body system organ class and by frequency. The frequency categories used are:
Very common > 1/10
Common > 1/100 to <1/10
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| System organ class | Very common | Common |
| Blood and lymphatic system disorders | Anaemia3 Neutropenia3 | Autoimmune haemolytic anaemia, autoimmune aplastic anaemia, autoimmune thrombocytopenia |
| Endocrine disorders | Hypothyroidism | Autoimmune thyroiditis |
| Nervous system disorders | Guillain-Barre syndrome | |
| Vascular disorders | Hypertension3 |
| System organ class | Very common | Common |
| Respiratory, thoracic and mediastinal disorders | Asthma, rhinitis allergic | |
| Hepatobiliary disorders | Autoimmune hepatitis | |
| Skin and subcutaneous tissue disorders | Dermatitis atopic, eczema | |
| General disorders and administration site conditions | Pyrexia | |
| Investigations | Hepatic enzyme increaseda, antinuclear antibody (ANA) positive, smooth muscle antibody positive | Antineutrophil cytoplasmic antibody positive |
aAdverse reactions considered potentially related to busulfan conditioning
Description of selected adverse reactions
Immune reconstitution
All the identified adverse reactions in the table (apart from those potentially related to busulfan) are considered to be related to immune reconstitution, due to their nature and timing. These autoimmune adverse reactions were reported for subjects post-gene therapy. The majority were reported during the 3 month to 3 year follow-up period and resolved, with the exception of hypothyroidism and positive ANA tests. In addition, the allergy related adverse reactions in the table were reported mostly during the 3 month to 3 year follow-up period.
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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseNo data from clinical studies are available regarding overdose of Strimvelis.
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
Strimvelis is an autologous cellular therapy. The nature of Strimvelis is such that conventional studies on pharmacokinetics, absorption, distribution, metabolism, and elimination are not applicable.
5.3 Preclinical safety data
5.3 Preclinical safety dataReproductive and developmental studies have not been conducted.
A 4-month biodistribution study was performed in mice. CD34+ cells derived from healthy human umbilical cord blood, transduced with the vector used for the production of Strimvelis, were administered intravenously to busulfan-conditioned mice. The majority of mice showed reconstitution of the haematopoietic system by the end of the study. Low levels of human cells and vector sequences were also detected in non-haematopoietic organs consistent with the presence of blood containing transduced human cells. There were no adverse effects on survival, haematological parameters or histopathology of major organs, apart from body weight loss and atrophy in the testes and ovaries consistent with administration of busulfan.
Carcinogenicity studies have not been conducted as no adequate animal model was available to evaluate the tumourigenic potential of Strimvelis due to the inability to achieve long-term engraftment of transduced cells in mice.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
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 hours.
6.4 Special precautions for storage
Store at 15–30°C.
6.5 Nature and contents of container
50 ml ethylene vinyl acetate (EVA) infusion bag, with a luer spike interconnector closed with a luer lock cap, packed in a re-usable outer container.
6.6 Special precautions for disposal
6.6 Special precautions for disposalStrimvelis is transported directly to the medical facility where the infusion will be administered. The infusion bag(s) is/are placed inside a closed outer container. The bags must be kept in the outer container until ready to use.
Strimvelis is intended solely for autologous use. The identity of the patient must be matched with the essential unique patient information on the primary and/or outer container prior to infusion.
Gently agitate the infusion bag to re-disperse any cellular aggregates, administer using a transfusion administration set with filter to remove any remaining cellular aggregates.
This medicinal product contains genetically-modified cells. Local biosafety guidelines applicable should be followed (see section 4.2).
Strimvelis is not tested for transmissible infectious agents. Healthcare professionals handling Strimvelis should therefore take appropriate precautions to avoid potential transmission of infectious diseases.
Work surfaces and material which have potentially been in contact with Strimvelis must be decontaminated with appropriate disinfectant.
Any unused medicinal product or waste material should be disposed of in accordance with local biosafety requirements.
Orchard Therapeutics (Europe) Ltd., 108 Cannon Street
London
EC4N 6EU
8 MARKETING AUTHORISATION NUMBER(S)
PLGB 49055/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
01/01/2021