Strimvelis - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Strimvelis 1–10 × 106 cells/mL dispersion for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION2.1 General description

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.

2.2 Qualitative and quantitative composition

The medicinal product is packaged in one or more infusion bags. Each patient-specific infusion bag of Strimvelis contains 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 × 106 CD34+ cells/mL.

Excipient with known effect

This medicinal product contains 0.15 mmol sodium per mL.

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 PARTICULARS4.1 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 sections 4.2 and 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. It should only be administered after consultation with the patient and/or family. Patients are expected to enrol in a post-treatment registry and will be followed-up long term.

Strimvelis is intended for autologous use only (see section 4.4).

A CD34+ stem cell back-up containing at least 1 × 106 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.

The patient must be able to donate sufficient CD34+ cells to deliver a minimum of 4 × 106 purified

CD34+ cells/kg, required for manufacture of Strimvelis.

Before infusion, it must be confirmed that the patient’s identity matches the essential unique patient information on the medicinal product 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 |jmol/L*miniite), the dose should be appropriately reduced based on the AUC.

Pre-medication

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 × 106 CD34+ cells/kg.

If the product contains less than 2 × 106 CD34+ cells/kg, the treating physician should decide 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 × 106 CD34+cell/kg.

Strimvelis should be administered once only.

Special populations

Elderly

This medicinal product is not intended for use in patients >65 years of age and has not been studied in this age group.

Renal impairment

This medicinal product has not been studied in patients with renal impairment. No dose adjustment is expected to be required.

Hepatic impairment

This medicinal product 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 or over 6 years and 7 months of age has not been established (see section 4.4). No data are available.

Method of administration

Strimvelis is for intravenous infusion only.

Precautions to be taken before handling or administering the medicinal product

Healthcare professionals should take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases when handling the product.

For instructions on preparation, accidental exposure and disposal of Strimvelis, see section 6.6.

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 50 mL syringe filled with a sodium chloride 9 mg/mL (0.9%) solution for injection should be used to flush the bag through.

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

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.

Autologous use

Strimvelis is intended solely for autologous use and should never be administered to any patient other than the original CD34+ cell donor.

Risk of insertional oncogenesis

One case of Lymphoid T cell leukaemia has been reported in a child with ADA-SCID 4.7 years after treatment with Strimvelis (see section 4.8).

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.

General

The long-term effects and durability of response to Strimvelis on ADA-SCID have not been systematically assessed beyond 8 years after treatment (see section 5.1).

Non-immunological manifestations of ADA-SCID may not respond to Strimvelis.

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 of the product has been established.

In some cases, the patient may be unable to receive treatment 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).

Warnings and precautions of the myeloablative conditioning medicinal products must be considered.

Immune reconstitution

During the clinical studies, T-lymphocyte (CD3+) and NK (CD56+) cell counts improved following treatment. Median values at 3-years post gene therapy were below the normal range. Continued follow-up is recommended.

Central venous catheter (CVC) complications including infections and thromboses

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.

Hypersensitivity and infusion-related reactions

This medicinal product should be used with caution in patients with hypersensitivity to aminoglycosides or bovine serum albumin.

Engraftment failure

There have been cases where treatment 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).

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.

Transmission of an infectious agent

A small risk of transmission of infectious agents exists. Healthcare professionals administering Strimvelis should therefore monitor patients for signs and symptoms of infections after treatment and treat appropriately, if needed.

Autoimmunity and immunogenicity

Patients with ADA-SCID can develop autoimmunity. In clinical studies, 67% (12 of 18) of treated patients had either autoimmune antibodies or other manifestations (e.g. autoimmune thrombocytopenia, autoimmune aplastic anaemia, autoimmune hepatitis and Guillain-Barre syndrome) (see section 4.8). Regular monitoring for clinical autoimmunity is recommended.

No immunogenicity testing has been conducted with Strimvelis.

Treatment of patients younger than 6 months and older than 6 years and 7 months

The treatment should be used with caution in patients younger than 6 months and older than 6 years and 7 months as there are no clinical data 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 treatment is also likely to be affected by residual thymic function which can become impaired in older children. Use of this medicinal product 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.

Serological testing

All patients should be tested for HIV-1/2, HTLV-1/2, HBV, HCV and mycoplasma prior to bone marrow harvest to ensure acceptance of the cellular source material for Strimvelis manufacturing.

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.

Blood, organ, tissue and cell donation

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.

After Strimvelis administration

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 the medicinal product has been infused, the treating physician will be notified. The physician should monitor and/or treat the patient as appropriate.

Sodium content

This medicinal product contains 42 to 137 mg sodium per dose, which is equivalent to 2 to 7% 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

No interaction studies have been performed. Strimvelis 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 following Strimvelis treatment has not been studied. Vaccination with live virus vaccines is not recommended during the 6 weeks preceding the start of non-myeloablative conditioning, and until haematological and immunological recovery following treatment with Strimvelis.

4.6 Fertility, pregnancy and lactation

As Strimvelis is not intended for use in adults, human data on use during pregnancy or lactation and animal reproduction studies are not available.

With regard to fertility, consult the SmPC of the conditioning medicinal product. It should be noted that the treating physician should inform the patient’s paren­ts/carers about options for cryopreservation of spermatogonial stem cells or ovarian tissue.

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 33 subjects i.e. 22 patients treated in the clinical development program and 11 patients treated in the commercial setting, with a median duration of follow-up of 12 years for patients treated in clinical studies and 1.5 years for patients treated in the commercial setting.

Given the small patient population and size of the cohorts, adverse reactions in the table below may not provide a complete perspective on the nature and frequency of these events. Serious adverse reactions include T-cell type acute leukaemia and 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), and common (>1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

aAdverse reactions considered potentially related to busulfan conditioning

Description of selected adverse reactions

Lymphoid T cells leukaemia due to insertional oncogenesis

Out of 33 patients with ADA-SCID treated with Strimvelis, one case of Lymphoid T cell leukaemia has been reported in one child (frequency: 3%). This event occurred 4.7 years after treatment with Strimvelis. Retroviral insertion site (RIS) analysis identified a single dominant clone located approximately 40 kb upstream of the LMO2 gene, a known oncogene, with an abundance > 98%.

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 national reporting system listed in

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, other immunostimulants, ATC code: L03AX.

Mechanism of action

After infusion, CD34+ cells engraft in the bone marrow where they repopulate the haematopoetic system with a proportion of cells that express pharmacologically active levels of the ADA enzyme.

Following successful engraftment in the patient, the effects of the product are expected to be life-long.

Pharmacodynamic effects

The median percentages of genetically modified cells in peripheral blood at one year and 3 years after treatment, for the patients enrolled in the pivotal study, were 28% (range 6%-92%) and 30% (range 8%-101%) of CD19+, and 73% (range 20%-100%) and 67% (range 39%-82%) of CD3+ cells, respectively. The median percentages of genetically modified cells in peripheral blood at year 8 for the patients enrolled in the long-term follow-up were 97% (range 1%-101%) of CD19+, and 101% (range 1%-101%) of CD3+ cells.

The presence of the transgene leads to increased expression of ADA. One-year post treatment, median ADA activity (mononuclear cells adenosine deaminase) in peripheral blood lymphocytes was 181.2 (range 42.11678.2) nmol/h/mg protein, compared to a baseline median (range) of 80.6 (30.5–92.3) nmol/h/mg protein. ADA activity remained increased throughout the duration of the 8 year follow up.

Clinical efficacy and safety

A total of 18 patients with ADA-SCID were treated with Strimvelis as part of one open-label pivotal trial (AD1115611; N=12), two early open-label pilot studies (AD1117054/AD­1117056; N=3), and a compassionate use program (AD1117064; N=3). Studies evaluated the use of Strimvelis with a range of 0.9 × 106 – 18.2 × 106 CD34+ cells/kg. All patients received busulfan conditioning prior to gene therapy, with most receiving a total dose of 4 mg/kg intravenously over 2 consecutive days prior to CD34+ infusion. Four subjects had previously received an unsuccessful stem cell transplant from a haploidentical donor and 15 of 18 subjects had previously received prior enzyme replacement therapy with polyethylene-glycol-modified bovine adenosine deaminase (PEG-ADA). Patients who previously received PEG-ADA had this treatment withdrawn 10 to 22 days prior to Strimvelis therapy. The median age across the program was 1.7 years (range 0.5 to 6.1) and 61% were males. Eighty three percent were white (56% Caucasian/European heritage and 28% Arabic/North African heritage), 11% African American/African, and 6% Asian.

Patients treated within the pivotal study

The efficacy of Strimvelis was evaluated in a 3-year open-label, prospective study in children who lacked a sibling HLA matched stem cell donor and were either failing to respond adequately to PEG-ADA, were intolerant or did not have access to it.

Results at 3 years for patients treated within the pivotal study are presented in Table 1. Treatment with Strimvelis resulted in a 100% survival rate at 3 years post therapy, a decrease in the severe infection rate, an increase in T-lymphocytes (CD3+) and all subjects having post-baseline venous red blood cell deoxyadenosine nucleotide (RBC dAXP) levels below pathological levels (>100 nmol/mL).

Table 1. Results at 3 years for the ITT population in the pivotal study*

* Including data from one patient collected post intervention with PEG-ADA (>3 months treatment) or hematopoietic stem cell transplantation

a Based on the entire pre-treatment period for severe infections (retrospectively collected), and the data collected at the baseline visit for T-lymphocytes. Patient 10 had no baseline value for T-lymphocytes.

b Based on the 3-year post-treatment period for survival and severe infections, and the data collected at the 3-year visit for T-lymphocytes and dAXP. Patient 8 withdrew from the study before 3-year visit, and thus had no data for T-lymphocytes and dAXP.

c Severe infections are those requiring or prolonging hospitalisation. The 3-month hospitalisation period immediately post gene therapy was excluded from the calculation

d dAXP=dAMP+dAD­P+dATP. dAXP results are based on a responder analysis of the percentage of patients following gene therapy who met the definition of adequate metabolic detoxification, therefore baseline value is not applicable. eAt baseline 9 of 11 (82%) patients had dAXP <100 nmol/mL. All these patients had previously taken PEG-ADA.

T cell function: In the patients treated in the pivotal study, T cell proliferation was demonstrated in response to stimulation with anti-CD3 antibodies (median 62629 cpm, range 4531 to 252173) and phytohemaglutinin (median 140642 cpm, range 11119 to 505607) at 1 year post gene therapy, and these responses were sustained through Year 3. Findings that TREC (T cell receptor excision circles) in peripheral blood lymphocytes were increased above baseline (median 141, range 56 to 1542 copies/100ng DNA) at Years 1 and maintained to 3 post-treatment and that all subjects had evidence of polyclonal V-beta chains at one or more time points following gene therapy provides further supportive evidence of functional T cell development.

B cell function: All 12 subjects treated in the pivotal study were receiving IVIG therapy at the time of screening, and 7 subjects (58%) had discontinued IVIG use during 0–3 years follow-up after gene therapy.

Long-term follow-up

A 100% survival rate was observed for all 12 subjects treated within the pivotal study and also for the 18 subjects in the integrated analysis, with a median follow up duration of approximately 12 years. Intervention-free survival in this pivotal population (defined as survival without the requirement for long-term (>3 month) re-introduction of PEG-ADA, or stem cell transplant) was 92% (11/12 subjects) (82% (14/17 subjects) for integrated population). One subject treated in a pilot study did not have PEG-ADA reintroduction data, and thus was excluded from the intervention-free survival in the integrated population. Long-term PEG-ADA (exceeding 3 months of continuous duration) was used by three subjects; two of these subjects subsequently received a sibling-matched stem cell transplant and one subject remained on chronic PEG-ADA treatment. Another subject needed transient PEG-ADA administration due to an autoimmune event (see section 4.4).

In those patients treated in the pivotal and long-term follow-up (LTFU) study, the rate of severe infections declined throughout the follow-up period (Table 2).

Table 2 Cumulative rate of severe infections per person year of exposure (combined pivotal and LTFU ITT population)

Excluding data from one patient from the Pilot 1 study who was not followed up until year 13 after gene therapy. n/a: not applicable.

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

Reproductive 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 reactions 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 PARTICULARS6.1 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 and other handling

Precautions to be taken when handling or administering the medicinal product

Healthcare professionals handling Strimvelis should take appropriate precautions (wearing gloves, protective clothing and eye protection) to avoid potential transmission of infectious diseases.

Strimvelis 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.

Precautions to be taken for the disposal of the medicinal product

Local guidelines on handling human-derived material should be followed for unused medicinal product or waste material. All material that has been in contact with Strimvelis (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local guidelines on handling human-derived material.

Accidental exposure

Accidental exposure to Strimvelis must be avoided. Local guidelines on handling of human derived materials should be followed in case of accidental exposure, which may include washing of the contaminated skin and removal of contaminated clothes. Work surfaces and materials which have potentially been in contact with Strimvelis must be decontaminated with appropriate disinfectant.

7. MARKETING AUTHORISATION HOLDER

Orchard Therapeutics (Netherlands) BV

Prins Bernhardplein 200,

1097 JB Amsterdam, the Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 May 2016

Date of latest renewal: