Source: European Medicines Agency (EU) Revision Year: 2017 Publisher: uniQure biopharma B.V., Meibergdreef 61, 1105 BA Amsterdam, The Netherlands
Pharmacotherapeutic group: Lipid modifying agents, other lipid modifying agents
ATC code: C10AX10
Glybera contains the human LPL gene variant LPLS447X 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 LPLS447X gene is promoted, by co-opting the expression machinery of the cell and the myocytes produce the protein product of the transgene LPLS447X without the vector being able to reproduce itself.
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.
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 appropriate CE marked test or full gene sequencing should be used to confirm the diagnosis.
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.
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 × 1012 gc/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.
This is an open-label study of alipogene tiparvovec at a fixed dose of 1x1012 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.
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.
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.
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.
Glybera is expected to be degraded by endogenous protein and DNA catabolic pathways.
Following intramuscular administration of Glybera to mice, vector DNA was transiently detected in the circulation. Eight days after administration, high levels of vector DNA sequence were detected in injected muscle and the draining lymph nodes. Except for the site of injection, the highest vector DNA copy numbers were found in the liver and blood. The lowest number of copies was found in the brain, lung, heart and non-injected groups of muscle. In gonads and reproductive organs, vector DNA copies were found at low levels. After time, residual vector DNA levels remained high in the injected muscle and inguinal lymph nodes while decreasing steadily in the other organs. The levels of Glybera vector DNA found in gonads were measurable but lower than in other non-target organs.
Immunosuppressant co-treatment did not influence the biodistribution pattern neither at low dose nor at high dose in mice. The biodistribution pattern was very similar in the other tested species (cats and rabbits).
Shedding was assessed in the clinical studies by collecting saliva, urine and semen. In CT-AMT-011-02 faeces was also collected. After administration of Glybera to the participants, the highest vector DNA concentrations were detected in the serum, with clearance by one to two logs per week.
In saliva vector DNA was still detectable up to 12 weeks; in urine up to 10 weeks and in semen up to 26 weeks. All but two patients received immunosuppressant for 12 weeks. There is the theoretical risk that the co-administration of the immunosuppressant regime leads to longer persistence of virus DNA in serum and as well to longer shedding in saliva, urine and semen.
High levels of vector DNA were observed up to 12 months after dosing in the target tissue for Glybera, injected leg muscle, but not in non-injected muscle.
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.
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.
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