Safety and Efficacy in LPL-Deficient Subjects of AMT-011, an Adeno-Associated Viral Vector Expressing Human Lipoprotein Lipase [S447X]

NCT01109498 | Unknown Phase 2 DMC

• 1 other identifier: CT-AMT-011-01
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Familial Lipoprotein Lipase Deficiency

Keywords

LPLD; Lipoprotein Lipase Deficiency; Chylomicronaemia; Genetherapy; AAV; Alipogene Tiparvovec; AMT-011; Lipoprotein Lipase

Outcome Measures

Primary Outcomes (2)

• Reduction of fasting triglyceride (TG) concentrations

  To achieve a reduction in fasting plasma TG such that the difference in median plasma TG observed before administration and up to 12 weeks after administration represents approximately 40% reduction, on top of a low-fat diet.

  12 weeks

• safety profile of AMT-011

  Between 6 and 15 years after administration of AMT-011, patients will be annually contacted by phone to monitor delayed adverse events related to administration of AMT-011.

  15 years

Secondary Outcomes (6)

• Reduction of TG concentrations

  26 weeks

• Reduction of TG concentrations

  12 weeks

• Reduction of TG concentrations

  26 weeks

• Biological activity and expression of the transgene product.

  1 year

• Evaluation immune respons

  5 years

Study Arms (3)

Dose cohort 3 x 10^11gc/kg

EXPERIMENTAL

intra muscular, 3 x E11 gc per kg body weight, injected in a single series of intramuscular injections

Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]

Alipogene Tiparvovec, Human LPL [S447X]

EXPERIMENTAL

intra muscular, 3 x E11 gc per kg body weight, injected in a single series of intramuscular injections with immunosuppressants

Drug: Mycophenolate mofetil; Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]; Drug: cyclosporine

Alipogene Tiparvovec, Human LPL [S447X], 1xE12 gc/kg

EXPERIMENTAL

intra muscular, 1 x E12 gc per kg body weight, injected in a single series of intramuscular injections with immunosuppressants

Genetic: Alipogene Tiparvovec (AMT-011), Human LPL [S447X]

Interventions

Alipogene Tiparvovec (AMT-011), Human LPL [S447X] GENETIC

intra muscular, 1 x E12 gc per kg body weight, injected in a single series of intramuscular injections

Also known as: Glybera, AMT-011

Alipogene Tiparvovec, Human LPL [S447X], 1xE12 gc/kg

Mycophenolate mofetil DRUG

oral, 2 g/day, day -3 till week 12

Also known as: CellCept

Alipogene Tiparvovec, Human LPL [S447X]

cyclosporine DRUG

oral, 3 mg/kg/day, day -3 till week 12

Also known as: Neoral

Alipogene Tiparvovec, Human LPL [S447X]

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

• Amsterdam Molecular Therapeutics: lead
• International Antiviral Therapy Evaluation Center: collaborator

Study Sites (1)

Ecogene-21 Clinical Trial Center/ Centre de santé et de services sociaux de Chicoutimi

Chicoutimi, Quebec, Canada

Location

Related Publications (7)

• Rip J, Nierman MC, Sierts JA, Petersen W, Van den Oever K, Van Raalte D, Ross CJ, Hayden MR, Bakker AC, Dijkhuizen P, Hermens WT, Twisk J, Stroes E, Kastelein JJ, Kuivenhoven JA, Meulenberg JM. Gene therapy for lipoprotein lipase deficiency: working toward clinical application. Hum Gene Ther. 2005 Nov;16(11):1276-86. doi: 10.1089/hum.2005.16.1276.

  PMID: 16259561 BACKGROUND

• Ross CJ, Twisk J, Meulenberg JM, Liu G, van den Oever K, Moraal E, Hermens WT, Rip J, Kastelein JJ, Kuivenhoven JA, Hayden MR. Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPL(S447X) beneficial mutation. Hum Gene Ther. 2004 Sep;15(9):906-19. doi: 10.1089/hum.2004.15.906.

  PMID: 15353045 BACKGROUND

• Ross CJ, Liu G, Kuivenhoven JA, Twisk J, Rip J, van Dop W, Excoffon KJ, Lewis SM, Kastelein JJ, Hayden MR. Complete rescue of lipoprotein lipase-deficient mice by somatic gene transfer of the naturally occurring LPLS447X beneficial mutation. Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2143-50. doi: 10.1161/01.ATV.0000176971.27302.b0. Epub 2005 Jul 7.

  PMID: 16002740 BACKGROUND

• Ross CJ, Twisk J, Bakker AC, Miao F, Verbart D, Rip J, Godbey T, Dijkhuizen P, Hermens WT, Kastelein JJ, Kuivenhoven JA, Meulenberg JM, Hayden MR. Correction of feline lipoprotein lipase deficiency with adeno-associated virus serotype 1-mediated gene transfer of the lipoprotein lipase S447X beneficial mutation. Hum Gene Ther. 2006 May;17(5):487-99. doi: 10.1089/hum.2006.17.487.

  PMID: 16716106 BACKGROUND

• Stroes ES, Nierman MC, Meulenberg JJ, Franssen R, Twisk J, Henny CP, Maas MM, Zwinderman AH, Ross C, Aronica E, High KA, Levi MM, Hayden MR, Kastelein JJ, Kuivenhoven JA. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2303-4. doi: 10.1161/ATVBAHA.108.175620. Epub 2008 Sep 18. No abstract available.

  PMID: 18802015 BACKGROUND

• Burnett JR, Hooper AJ. Alipogene tiparvovec, an adeno-associated virus encoding the Ser(447)X variant of the human lipoprotein lipase gene for the treatment of patients with lipoprotein lipase deficiency. Curr Opin Mol Ther. 2009 Dec;11(6):681-91.

  PMID: 20072945 BACKGROUND

• Gaudet D, Methot J, Dery S, Brisson D, Essiembre C, Tremblay G, Tremblay K, de Wal J, Twisk J, van den Bulk N, Sier-Ferreira V, van Deventer S. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther. 2013 Apr;20(4):361-9. doi: 10.1038/gt.2012.43. Epub 2012 Jun 21.

  PMID: 22717743 DERIVED

MeSH Terms

Conditions

Hyperlipoproteinemia Type I

Interventions

Alipogene tiparvovec; Mycophenolic Acid; Cyclosporine

Condition Hierarchy (Ancestors)

Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2010
• First Posted: April 23, 2010
• Study Start: August 1, 2007
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: September 30, 2011

Record last verified: 2010-04

Locations

CA (1)