safety and efficacy in lpl-deficient subjects of amt-011, an adeno-associated viral vector expressing human lipoprotein lipase [s447x]

Conditions: Familial Lipoprotein Lipase Deficiency

Summary: lpld is a rare autosomal recessive disorder, characterized by the presence of marked chylomicronemia and hence hypertriglyceridemia. clinically the most severe manifestation of chylomicronemia, is acute pancreatitis, which can be lethal. there is no effective therapy available to modulate the course of the illness and prevent complications for these patients. the current clinical management consists of severe reduction of dietary fat that is hard if not almost impossible to comply with. lpld subjects continue to experience pancreatitis attacks, and are admitted to intensive care units on several occasions. alipogene tiparvovec corrects or restores lipoprotein lipase (lpl) function long term, and hence reverses some symptoms, halts the disease progression and prevents further complications. alipogene tiparvovec gene therapy ensures that a catabolically beneficial variant of the human lpl gene, lpl\[s447x\] is expressed and active in the relevant tissues in humans. delivery of the gene is realized via intramuscular injection of an adeno-associated viral vector, pseudotyped with aav1 capsids.

the ct-amt-011-01 study is an open-label, dose-escalating study evaluating the safety and efficacy of a single intramuscular administration of amt-011 (at multiple sites). the study will be performed in the community genomic medicinecenter (cgmc) chicoutimi, canada, under the supervision of their medical ethical committee and according to the local biosafety procedures. the study participants will be treated under the responsibility of a principal investigator specialised in the treatment of lipid disorders. a total number of 14 subjects will be administered. participants will be screened 3 weeks prior to administration of amt-011 and will be evaluated for 12 weeks post administration in this study. after the study, subjects will be followed up long term with particular emphasis on the safety and efficacy aspects of lpl gene therapy using amt-011. subjects will be evaluated at the clinical site at 19 weeks, 26 weeks, 39 weeks, 1 year, 1.5 years, 2 years, 3 years, 4 years and 5 years after administration of amt-011. the tg values that are obtained at week 26 will be used for secondary efficacy analysis.

Eligibility criteria:
inclusion criteria: * eligible population study participants must have participated in the preceding observation study (prep-02: appendix iii) and be diagnosed with lipoprotein lipase deficiency, meeting the following criteria: (i) their lipoprotein lipase activity levels in post-heparin plasma should be ≤20 % of normal; (ii) confirmed homozygocity or compound heterozygocity for mutations in the lpl gene; (iii) post-heparin plasma lpl mass should be \>5% of normal; (iv) median fasting plasma tg concentrations \>10.00mmol/l, as determined on the basis of 5 consecutive time points in the preceding observation study with a history of pancreatitis. * general health the participant must be in good general physical health with, in the opinion of the investigator, no other clinically significant and relevant abnormalities of medical history, and no abnormalities at the physical examination and routine laboratory evaluation performed prior to the trial. * age age ≥18 years old. * sex male or female. females must be of non-child bearing potential or with a negative pregnancy test and not breast feeding. female subjects must use appropriate contraception (if relevant) and their spouse must use barrier contraception for the duration of the study (12 weeks). males must practice barrier birth control and their spouse should use appropriate contraception until three consecutive semen samples, taken at least 75 days after administration, are negative for amt-011 vector dna. * compliance the participant is willing to fully comply with all study procedures and requirements of the trial such as restrictions to a low-fat diet (see section 8.1). * consent the participant has the mental ability to give voluntary written informed consent to participate in the study. exclusion criteria: * disease * apolipoprotein cii deficiency. * inflammatory muscle disease (e.g. myositis, myopathies or rhabdomolysis). * any current or relevant previous history of serious, severe or unstable physical or psychiatric illness, any medical disorder that may make the participant unlikely to fully complete the study, or any condition that presents undue risk from the study medication or procedures (e.g. malignant neoplasia). * active infectious disease of any nature, including clinically active viral infections. * laboratory parameters the following blood screening tests will result in exclusion from participation: * platelet count \< 100 x 109 /l. * hemoglobin \< 7.0 mmol/l. * liver function disturbances (bilirubin \>2.50 x normal, transaminases \>3 x uln). * cpk \> 3 x uln. * creatinine \> 3 x uln.

Keywords: lpld lipoprotein lipase deficiency chylomicronaemia genetherapy aav alipogene tiparvovec amt-011 lipoprotein lipase