Glybera - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Glybera 3 × 1012 genome copies/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION2.1 General description

Alipogene tiparvovec contains the human lipoprotein lipase (LPL) gene variant LPLS447X in a vector.

The vector comprises a protein shell derived from adeno-associated virus serotype 1 (AAV1), the Cytomegalovirus (CMV) promoter, a woodchuck hepatitis virus posttranscriptional regulatory element and AAV2 derived inverted terminal repeats. Alipogene tiparvovec is produced using insect cells and

recombinant baculovirus technology.

2.2 Qualitative and quantitative composition

Each vial of alipogene tiparvovec contains 1 extractable ml of solution, containing 3 × 1012 genome copies (gc). .

Each patient-specific pack contains a sufficient amount of vials to dose each patient with 1 × 1012 LPLS447X gc/kg bodyweight.

Excipient with known effect:

This medicinal product contains 47.5 mg sodium per administration at 27 injection sites to 105.6 mg sodium per administration at 60 injection sites.

For the full list of excipients, see section 6.1.

scent, colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Glybera is indicated for adult patients diagnosed with familial lipoprotein lipase deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The diagnosis of LPLD has to be confirmed by genetic testing. The indication is restricted to patients with detectable levels of LPL protein (see section 4.4).

4.2 Posology and method of administration

Glybera should only be used when the diagnosis of LPLD has been confirmed by an adequate genetic test (see section 5.1).

Glybera therapy must be prescribed by and administered under the supervision of a physician with expertise in treating LPLD patients and in gene therapy administration, in full consultation with the patient. During administration of Glybera appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration.

Posology

The maximum total dose of Glybera for administration is 1 × 1012 gc/kg body weight.

Glybera is authorised for single treatment only. No data on re-administration of Glybera are available, therefore Glybera should not be re-administered.

Glybera is administered as a one-time series of intramuscular injections in the legs. The dose per injection site is 1.5 × 1012 gc, or 0.5 ml of solution for injection. For each injection site, one syringe of 1 ml with clear volume marks of 0.5 ml must be used. Volumes per injection site must not exceed 0.5 ml. Syringes must not be used more than once.

The treatment should be monitored by measuring neutralising antibodies and T-Cell response against AAV1 and LPLS447X and T-Cell response at baseline as well as 6 and 12 months after treatment.

To calculate the number of vials, the patient’s weight is determined to the nearest whole kg. The patient’s weight should be divided by 3, and rounded up to the next higher whole number. This is the number of vials that must be dispensed.

To calculate the number of injection sites and the number of syringes, the patient’s weight is determined to the nearest whole kg. The patient’s weight should be divided by 3, then without rounding up this number multiplied by 2 and rounded up to the next higher whole number. This is the number of injection sites and the total number of syringes (each filled with 0.5ml) required for the patient’s tre­atment.

Examples of typical dose schedules based on the body weight of patients are shown in the table below:

Body weight (kg)	Number of vials (1 mL) ex	Number of 1 ml syringes (each filled) with 0.5 ml)	Number of injection sites
40	4 14	27	27
50	17	34	34
60	20	40	40
65	Çx 22	44	44
70	24	47	47
75Ct	25	50	50
80 $	27	54	54
90	30	60	60

From three days prior to and for 12 weeks following Glybera administration an immunosuppressive regimen should be administered: ciclosporin (3 mg/kg/day) and mycophenolate mofetil (2 × 1 g/day) is recommended.

In addition, half an hour prior to Glybera injection an intravenous bolus of 1mg/kg of methylprednisolone should be administered (see section 4.4).

Paediatric population

The safety and efficacy of Glybera in children and adolescents below 18 years has not been established. No data are available.

Elderly

There is limited experience in the use of Glybera in elderly subjects. No dose adjustment of Glybera is necessary in the elderly population.

Dose of immunosuppressant may need to be adjusted.

Renal impairment or hepatic impairment

There is limited experience in the use of Glybera in patients with renal or hepatic impairment.

No dose adjustment of Glybera is required.

Method of administration

Upon intramuscular injection, the patient will receive multiple injections of 0.5 ml (one injection per syringe), distributed over the muscles of both upper and lower legs, under aseptic conditions such as iodine.

Spinal or regional anaesthesia is advised prior to intramuscular administration, due to the numb injections required. In case of contraindication for such procedure deep sedation is advised inste

Glybera should under no circumstances be administered intravascularly (see section 4.4).

To ensure intramuscular injection, ultrasound or electrophysio­logical guidance of injections is advised.

The instructions for use, handling and disposal are given in section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients of Glybera listed in section 6.1.

Immunodeficiency

Anti-platelet or other anti-coagulant medicinal products must not be used concomitantly with Glybera at the time of injection and for at least one week before or one day after the injection.

Oral contraceptive use (see section 4.6).

This medicinal product contains_gene­tically-modified organisms. Local biosafety guidelines applicable for such products should be followed (see section 6.6).

Glybera should only be administered to patients with an LPL protein mass of at least 5% of normal. LPL protein mass should be determined by ELISA or equivalent methods. LPL protein mass should be measured in a blood sample from the patient against a control sample from healthy volunteers.

Diet

Treatment with Glybera does not eliminate attacks of acute pancreatitis. Patients are advised to continue to follow a low-fat diet and refrain from alcohol consumption.

Diabetic patients

Limited data are available in diabetic patients. Diabetes mellitus is common in patients who have the most severe symptoms of LPLD. The opportunity to treat diabetic patients suffering from LPLD should be carefully considered by the physician.

Immunosuppres­sants (see section 5.2)

Immediately prior to initiation of the immunosuppressant regimen and prior to Glybera injection the patient must be checked for symptoms of active infectious disease of any nature, and in case of such infection the start of treatment must be postponed until after the patient has recovered.

Thromboembolic events

LPLD involves a state of hyperviscosity/hy­percoagulabili­ty. Spinal anaesthesia and multiple intramuscular injections may further increase the risk of (thrombo) embolic events at and shortly after administration of Glybera. Assessment of each individual subject’s risk profile prior to Glybera administration is advised. Follow applicable local or international guidelines for prophylaxis (See also section 4.5).

Cell and tissue donation

Treated patients should not donate blood, organs, tissues and cells for transplantation. This information is also provided in the Glybera Patient’s Aler­t Card.

Serum creatine kinase

Recipients of Glybera may display a rise in serum creatine kinase activity that becomes 2 weeks after administration, peaks at around 8 weeks and then returns to baseline by week 26. One

patient developed myoglobinuria in association with raised serum creatine kina

Muscle biopsies obtained up to 52 weeks after administration of Glybera show an infiltrate of lymphocytes and macrophages. The long term consequences of this cellular infiltration are not known.

Sodium content and potassium content

This medicinal product contains 47.5 mg sodium per administration at 27 injection sites to 105.6 mg sodium per administration at 60 injection sites. To be taken into consideration by patients on a controlled sodium diet.

The product contains less than 1 mmol (39 mg) potassium per administration of 27–60 injection sites ; i.e. essentially potassium-free.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies other than preclinical and clinical studies with mycophenolate mofetil and ciclosporin have been performed.

Anti-platelet or other anti-coagulant medicinal products must not be used concomitantly with Glybera at the time of injection. Correction of bleeding parameters should be instituted prior to Glybera administration. Anti-platelet or other anti-coagulant medicinal products must not be taken for at least one week before the leg injections or one day after the injection (see section 4.3).

Oral contraceptive use is contraindicated in LPLD patients (see section 4.3) as this may exacerbate the underlying disease.

4.6 Fertility, pregnancy and lactation

Contraception in males and females

Women of childbearing potential must be advised to use reliable barrier contraception methods in accordance with the guidelines for immunosuppressants for a minimum of 12 months from the start of therapy (9 months following cessation of immunosuppres­sants). Therefore, use of barrier contraception methods for at least 12 months following Glybera administration is recommended.

Oral contraceptive use is contraindicated in LPLD patients (see section 4.3) as this may exacerbate the underlying disease.

Male patients, including vasectomised males, are advised to practise barrier contraception methods for at least 12 months following Glybera administration.

Pregnancy

Very limited data on pregnancies exposed to Glybera is available. Animal studies do not indicate any harmful effects on pregnancy or embryonal/foetal development from Glybera (see section 5.3). Glybera should not be administered to pregnant women unless the possible benefit to the mother outweighs the possible risk to the foetus.

Breast-feeding

It is not known whether Glybera is excreted in human milk. Glybera should not be administered to women who are breast-feeding as long as breastfeeding is ongoing.

Fertility

No clinical data on the effect of Glybera on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.

4.7 Effects on ability to drive and use machines

Glybera has minor influence on the ability to drive and use machines, dizziness was commonly

observed after Glybera administration (see section 4.8). Patients experiencing dizziness are advised to not drive or use machines.

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reaction is pain in extremity occurring in approximately one third of patients. One patient was diagnosed with pulmonary embolism 7 weeks after therapy. Given the small patient population and size of the cohorts, captured adverse reactions and serious adverse reactions do not provide a complete perspective on the nature and frequency of these events.

Tabulated list of adverse reactions            zAJ

Adverse reactions are listed below by MedDRA body system organ class and by frequency. Very common (>1/10); common (>1/100 to <1/10/; uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Jy

MedDRA System Organ Class	Very common cy	Common
Metabolism and nutrition disorders		Decreased appetite
Nervous system disorders	Headache	Burning sensation, Dizziness, Formication, Presyncope
Vascular disorders		Hypertension
Respiratory, thoracic and mediastinal disorders		Dyspnoea exertional, Pulmonary embolism
Gastrointestinal disorders		Abdominal pain.Nausea, Constipation
Skin and subcutaneous tissue disorders		Hair growth abnormal, Palmar-plantar erythrodysaesthesia syndrome, Rash
Musculoskeletal and connective tissue disorders	Pain in extremity	Arthritis, Limb discomfort, Muscle spasms, Muscle strain, Musculoskeletal stiffness, Myalgia, Muscle pain, Neck pain, Sensation of heaviness, Acute myositis and chronic myositis
General disorders and administration site conditions	Fatigue, Hyperthermia	Chills, Injection site pain, Oedema peripheral, Pyrexia

Investigations	Elevations in serum creatine kinase activity
Injury, poisoning, and procedural complications	Contusion	Injection site discomfort, Injection site oedema, Injection site pruritus

Immunogenicity

An immune response was seen despite the use of immunosuppressants.

In clinical trials with Glybera, antibodies against the adeno-associated virus (AAV) protein shell were present prior to treatment, in 18 out of 27 subjects; anti-AAV antibodies appeared or increased after Glybera administration, in all of the subjects. The clinical relevance of the antibody response is unknown (see section 4.2 on re-administration).

No neutralising assay was used.

T-cell responses against AAV were detected in approximately half of the subjects post therapy only. No T-cell response to LPL was detected in any subject.

With the exception of a case of fever (39.9 °C) in study CT-AMT-011–01 which reversed within a day, no Glybera or immunosuppression related serious adverse events occurred.

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 Appendix V.

4.9 Overdose

Pre-clinical studies with doses ten times the recommended dose (1 × 1013 gc/kg) did not lead to any general systemic untoward signs or symptoms. Symptomatic and supportive treatment, as deemed necessary by the treating physician, is advised in case of overdose.

In the event two doses are administered by mistake to the identical injection site this might lead to more local reaction such as bruising or sensitivity.

Local pain or sensitivity may be managed by symptomatic treatment such as administration of local or systemic pain relievers.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Lipid modifying agents, other lipid modifying agents, ATC code: C10AX10.

Mechanism of action

Glybera contains the human LPL gene variant LPL S447X in an adeno-associated virus serotype 1 (AAV1) vector intended to target the muscle. Glybera is injected as a one-time series into the muscle of the lower extremities where it is taken up by myocytes. The elements of the vector were chosen such that expression of the LPL S447X gene is promoted, by co-opting the expression machinery of the cell and the myocytes produce the protein product of the transgene LPL S447X without the vector being able to reproduce itself.

Pharmacodynamic effects

Lipoprotein lipase is a key ‘first step’ enzyme in the metabolism of lipoproteins following fat intake with diet. In clinical studies a transient reduction in triglycerides for up to 12 weeks in individual patients could be observed. Furthermore, Glybera allows expression of the LPL protein in injected muscle which is reflected by the improvement of postprandial chylomicron (CM) metabolism observed in a small subset of patients.

Clinical efficacy and safety

The clinical efficacy and safety of Glybera has been evaluated in three interventional clinical studies with AAV1-LPLS447X in LPLD subjects.

Two of these clinical trials were preceded by prospective observational studies to assess fasting triglycerides (TG) level and symptoms and signs of LPLD in subjects maintained on a low fat diet.

Strict compliance with dietary fat restriction was difficult.

Standard genetic analysis (sequencing) was used in the clinical studies of Glybera. An appropri marked test or full gene sequencing should be used to confirm the diagnosis.

Clinical trial CT-AMT-010–01

AAV1-LPLS447X was administered to 8 LPLD patients in a 12-week, open label dose escalating study (1 × 1011 gc to 3 × 1011 gc per kg body weight i.m.). No drug-related serious adverse events occurred and no dose-limiting toxicity was observed. In half of the subjects a T-cell response to the vector was seen. Compared to pre-administration, a transient and variable reduction in median triglyceride levels was recorded for all patients.

Clinical trial CT-AMT-011–01

The aim of this open label, dose escalating study was to assess the safety profile and reduction of fasting plasma triglyceride (TG) levels after 12 weeks post Glybera administration in 14 LPLD patients. All patients were controlled on low fat diets in the 12-week main study period. The first 2 patients enrolled received a dose of 3 × 1011 gc/kg, the next 4 patients received a dose of 3 × 1011 gc/kg with immunosuppressant regiment (oral ciclosporin and oral mycophenolate mofetil from the day after Glybera administration until Week 12) and the final 8 patients received a dose of 1 × 1012gc/kg with immunosuppressant regiment. T-cell responses were seen in roughly half of the patients without clinical sequelae. From the triglyceride data the 1 × 1012 gc/kg dose appears the most optimal.

Clinical trial CT-AMT-011–02

This is an open-label study of alipogene tiparvovec at a fixed dose of 1×1012 gc/ kg body weight administered by a single series of intramuscular injections. Five eligible subjects were included in the study with all subjects receiving alipogene tiparvovec. Subjects also received a daily oral dose of 3 mg/kg/day cyclosporine and 2 g/day of mycophenolate mofetil starting three days before administration of alipogene tiparvovec through week 12. A single intravenous bolus of methylprednisolone (1 mg/kg bodyweight) was given 30 minutes prior to alipogene tiparvovec administration. One patient was diagnosed with pulmonary embolism 7 weeks after therapy. A transient reduction of triglycerides for up to 12 weeks in some individual patients has been observed. After this time, triglyceride levels reverted back to baseline. A demonstrable improvement of postprandial CM metabolism was shown in 5/5 patients up to week 14 and in 3/3 patients who were followed up to 52 weeks.

All interventional studies continued into long term follow up studies. The patients in CT-AMT-010–01 have been followed for up to 5 years (n=6) post therapy administration, those in CT-AMT-011–01 for up to 5 years (n=13), and those in CT-AMT-011–02 for up to 1 year (n=3).

Muscle biopsies taken half a year post administration demonstrated long-term expression of the LPL gene and the presence of biologically active LPL protein.

Clinical trial CT-AMT-11–03

Study CT-AMT-011–03 was a combined retrospective and prospective study of subjects who had taken part in studies CT-AMT-10–01, CT-AMT-11–01, CT-AMT-11–02.

In a follow-up period of up to 3 years after treatment, there was a decreasing trend in the incidence and severity of pancreatitis in the 12 patients who had multiple attacks during their life time.

Clinical trial CT-AMT-11–05

Further follow-up of patients who took part in study CT-AMT-11–03 (to a median of 5.8 years after exposure to Glybera) has shown a reduction in hospital stay of 1 day per patient per year when compared to the same length of time prior to exposure.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Glybera in all subsets of the paediatric population in the treatment of lipoprotein lipase deficiency (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Glybera is expected to be degraded by endogenous protein and DNA catabolic

Pharmacokinetics in special populations e.g. elderly/renal impairment etc.

Glybera is injected directly into the target organ, skeletal muscle. Liver and kidney function, cytochrome P450 polymorphisms and ageing are not expected to influence the clinical efficacy or safety of Glybera.

5.3 Preclinical safety data

Upon injection, Glybera was well tolerated in all animal studies performed with no notable clinical signs. In mice local cellular infiltrates and signs of degeneration and regeneration without necrosis, were seen at the clinical dose in the injected muscle upon histopathological examination. These effects were dose-dependent but showed regression with time. As expected, all animals developed antibodies to the AAV protein shell.

Upon treatment four weeks prior to mating, no maternal, foetal and developmental toxicity was seen in mice. No vector DNA could be detected in the foetuses after treatment of either the females or the males prior to mating.

Carcinogenicity studies have not been conducted. However in toxicity studies, no increase in tumour was identified. Although there is no fully adequate animal model to address the tumourigenic potential, the available toxicological data do not suggest any concern for tumourigenicity

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Disodium phosphate anhydrous

Potassium chloride

Potassium dihydrogen phosphate

Sodium chloride

Sucrose

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life 18 months for frozen vials.

Once thawed the medicinal product must be     immediately; if not used immediately, the vials

should be stored in a refrigerator at 2°C to 8°C, and protected from light for a maximum of 8 hours. Once thawed, the medicinal product should not be re-frozen.

If not stored in a refrigerator the medicinal product can be stored in syringes at not more than 25°C, and protected from light for a maximum of 8 hours.

Store and transport vial frozen –25oC to –15oC.

Keep the vial in the outer carton in order to protect from light.

6.5 Nature and contents of container and special equipment for use, administration or implantation

1 ml solution in a 2 ml vial (glass) with siliconised chlorobutyl, injection stopper and flip-off seal.

Each preformed transparent sealed plastic casing contains either 2 or 3 individual vials with a liquid absorbing sheet. The final outer carton contains a variable number of casings according to the patient specific dose required.

6.6 Special precautions for disposal and other handling

Instructions for preparation and handling and disposal

Refer to local biosafety guidelines applicable for handling and disposal of medicinal products containing genetically-modified organisms.

Work surfaces and material which have potentially been in contact with Glybera must be decontaminated with appropriate virucidal disinfectants with activity for non-enveloped viruses (such as hypochlorite and chlorine releasers) for at least 10 minutes.

Preparation of Glybera for administration

After the amount of Glybera to be administered has been calculated (see section 4.2) remove the correct number of single use vials from the freezer to thaw at room temperature (15oC to 25oC), approximately 30–45 minutes in advance of syringe filling.

After thawing, each vial should be gently inverted twice to ensure even mixing. Vials should be visually inspected for particulate matter and colour. The clear to slightly opalescent and colourless solution must be free of visible particles. Only clear and colourless solutions without visible particles should be used. If a vial is showing damage, syringes for the injection should not be prepared and the injection procedure should be postponed and rescheduled. The Marketing Authorisation Holder should be informed immediately.

Glybera is delivered in a patient-specific pack and will therefore contain the precise amount of vials per patient, calculated according to the patient’s weight.

The calculated amount of syringes should be filled from the thawed vials, and they should be labelled and placed in a container protected from light suitable for transportation to the room where the patient will undergo the intramuscular injections.

To avoid any injection of particles from the stopper due to two wit withdrawal from the vial (to be left inside the stopper) and a sep used.

7. MARKETING AUTHORISATION HOLDER

uniQure biopharma B.V. Meibergdreef 61 1105 BA Amsterdam The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 October 2012