Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency

doi:10.1016/j.atherosclerosissup.2010.03.004

Atherosclerosis Supplements

Volume 11, Issue 1, June 2010, Pages 55-60

https://doi.org/10.1016/j.atherosclerosissup.2010.03.004 Get rights and content

Abstract

Alipogene tiparvovec (AAV1-LPL^S447X) gene therapy is developed to prevent complications and decrease the clinical morbidity of lipoprotein lipase deficiency (LPLD). LPLD is an autosomal recessive disease associated with severe hypertriglyceridemia (hyperTG), severe chylomicronaemia, and low HDL. Acute pancreatitis, the most frequent serious clinical LPLD complication, is a complex and heterogeneous inflammatory condition having many causes including hyperTG and chylomicronaemia. In many patients, low fat diet and currently available lipid lowering drugs are ineffective to prevent hyperTG or pancreatitis in LPLD. The clinical development program of alipogene tiparvovec includes observational studies as well as phase I/II and II/III clinical trials. Pooled data are collected on safety and efficacy issues, including the incidence of pancreatitis.

Introduction

Lipoprotein lipase deficiency (LPLD) is characterized by the inability of affected individuals to produce functionally active lipoprotein lipase (LPL). LPL is mainly produced in skeletal muscle, fat tissue, and heart muscle [1] and has multiple key functions, among which is the catabolism of triglyceride (TG)-rich lipoproteins, chylomicrons (CM) and very low-density lipoproteins (VLDL). Off-loading TG from CM (and VLDL) normally protects against excessive post-prandial rise in chylomicron mass and TG. In LPLD, LPL is dysfunctional and more than 12 h after meals hyperTG and chylomicronaemia are still present and visible as lipemia.

LPLD is an autosomal recessive disorder caused by loss-of-function mutations in the LPL gene. The LPL gene is located on chromosome 8p22 and comprises 10 exons. To date, more than 70 LPL gene mutations have been described, most of them associated with loss of catalytic function [2]. Patients are either homozygous for such mutations or compound heterozygous. In a few areas in the world, such as in South Africa and Eastern Quebec, the disease is more common, because of a “founder” effect, with the majority of diagnosed patients having the same few mutations [3]. The prevalence outside of founder populations is estimated to be 1–2 in a million of the population, and hence it is an orphan disease.

LPLD is the most common Mendelean cause of (hyper)chylomicronaemia. Other causes include Apolipoprotein CII (APOC2) or Glycosylphosphatidylinositol Anchored High Density Lipoprotein Binding Protein 1 (GPIHBP1) deficiency [4]. Some cases due to circulating anti-LPL antibodies have been reported [5]. As phenotypic presentation of LPLD may overlap with that of other causes of chylomicronaemia genetic diagnosis in this day and age may be the preferred way to establish the diagnosis definitively.

In LPLD, extreme concentrations of circulating large chylomicrons (chylomicronaemia) are present, which are thought to be responsible for causing most of the clinical manifestations. LPLD may present during infancy or childhood with (repeated) severe abdominal pain episodes or failure to thrive [1], [6], [7]. On physical examination, eruptive xanthomas, lipaemia retinalis, and hepatosplenomegaly may be detected. The most severe manifestation is acute pancreatitis, which can be lethal. Diabetes is another complication seen frequently in LPLD, and may be due to recurrent pancreatitis, ultimately resulting in endocrine as well as exocrine pancreatic insufficiency [1], [8], [9] and/or by impaired ‘energy metabolism and distribution’ related to broad LPL dysfunction in various tissues. Premature atherosclerosis can occur [10].

Fasting lactescent plasma often is the trigger to further work up and ultimate diagnosis. The severity of the symptoms being roughly proportional to level of chylomicronaemia, usually measured as whole plasma TG; TG concentrations above 10 mmol/L have been suggested to be critical levels [1] below which the risk of pancreatitis would be substantially reduced.

Currently, no drug therapy for LPLD is available, and patients are managed by a severely fat-restricted diet, which however does not fully eliminate the risk of pancreatitis or disease progression. Alipogene tiparvovec is being developed to control the symptoms and prevent complications of LPLD.

Section snippets

Lipoprotein lipase deficiency (LPLD) and pancreatitis

Acute pancreatitis is a heterogeneous inflammatory condition, which leads to significant morbidity or mortality in 20–30% of patients [11]. There are several genes associated with susceptibility to acute pancreatitis, which include the cationic trypsinogen (PRSS1 and PRSS2), chymotrypsinogen C (CTRC), pancreatic secretory trypsin inhibitor (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-sensin receptor (CASR) [12], [13], [14], [15]. Although not being the only

Conventional clinical management of LPLD

Clinical management of LPLD patients currently consists of severe reduction in dietary fat to less than 20% of caloric intake and the use of medium-chain TG. It is almost impossible to always, life-long, comply with such a dietary regimen. As shown in Fig. 2, even when LPLD patients are compliant to the diet and are tightly followed in a lipid clinic by a dietician and a medical team, TG do not decrease below the threshold of increased pancreatitis risk. In the prospective observational studies

Alipogene tiparvovec

Alipogene tiparvovec [Glybera^®; AMT-011; AAV1-LPL^S447X] contains the human LPL gene variant LPL^S447X (the active component). The LPL^S447X ‘gain-of-function’ variant is found in 20% of Caucasians and is associated with enhanced removal of proatherogenic apoB100-containing particles, including LDL-cholesterol [20], lower plasma TG levels, higher HDL cholesterol concentrations, and lower rates of cardiovascular disease, when compared to the general population [20], [21]. In addition, it may have

Alipogene tiparvovec is provided as a solution for intramuscular injection

AAV1-LPL^S447X, initially designated AMT-010, was previously produced in a mammalian cell system which was not appropriate for large-scale production. Hence, this method has been superseded by a more efficient production system to produce alipogene tiparvovec (AMT-011).

Preclinical studies

Proof of principle of the efficacy of gene therapy with AAV1-LPL^S447X was obtained in LPL deficient mice and cats. Intramuscular (IM) delivery of AMT-010 or AMT-011 to LPL deficient animals resulted in >95% reduction in plasma TG. In mice, the effect was long-term, lasting over a year, and was dose-dependent, with full correction of lipemia and reduction of plasma TG to near-normal levels at a dose of 1 × 10¹³ genome copies (gc)/kg. The safety studies of AMT-010 and AMT-011 showed both products

Clinical development program

LPLD is a very rare condition (prevalence worldwide 1–2 per million). As with most very rare conditions, the presentation and phenotypes, natural history and evolution, morbidity and mortality, and effects of therapies and interventions are incompletely understood. Therefore, prospective observational studies to document the natural history, presentation, evolution and burden of disease were included in the clinical development program. Not only were values for TG established, to assess the

Additional studies and pooled data on the incidence of pancreatitis in LPLD

The clinical development of alipogene tiparvovec started in 2005. All participants to the CT-AMT-010-01, 011-01 and 011-02 trials are intended to be followed for 15 years after dosing in a registry. This long-term follow-up will allow the ongoing assessment of safety and efficacy of gene therapy with AAV1-LPL^S447X which includes continued collection of data on the incidence of pancreatitis. Modeling of pancreatitis data available from the entire program until October 2009, using a Cox

Risk assessment and ethical issues

In addition to long-term efficacy follow-up, specific features of risk associated with AAV1-LPL^S447X gene transfer will be monitored over years. The objective is to strike the most appropriate balance between efficacy (reduced risk of pancreatitis and other LPLD co-morbidities) and safety (risk of severe adverse events) [31], [32]. For both efficacy and safety issues, risk is defined as the probability over time that an event is due to hazard or exposure [33]. The notion of risk is closely tied

Summary

LPLD is a serious chylomicronemic disorder. LPLD is associated with increased coronary artery disease and diabetes risk, but the most debilitating complication is pancreatitis. Acute pancreatitis is a complex, heterogeneous, highly morbid and potentially fatal disease. Efficacy results from the clinical studies on AAV1-LPL^S447X appear promising, especially regarding reduced risk of acute pancreatitis events. In these studies, alipogene tiparvovec was in general well tolerated and safe. Further

Conflict of interest statement

All co-authors have been directly involved in the clinical development program of alipogene tiparvovec. JdW, AF and SvD are AMT employees. DG was the principal investigator for AMT-011-01 and AMT-011-02 studies and has received honoraria from AMT. SD was co-investigator in these studies and received honoraria for his involvement. JM was the AMT-011-01 and AMT-011-02 trials clinical pharmacist and has received honoraria for her participation. DB and KT are involved in the execution and the

Acknowledgements

Authors are thankful to all participants in the clinical studies and to the staff of the Academic Medical Center in Amsterdam, the ECOGENE-21 Clinical Research Center in Chicoutimi and Amsterdam Molecular Therapeutics (AMT) B.V. J. Méthot is a Université de Montréal post-doctoral fellow, received support from the Canadian Institutes of Health Research (CIHR). K. Tremblay is a Université de Montréal post-doctoral and CCRP fellow and receives support from ECOGENE-21. D. Gaudet holds the Canada

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Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency

Abstract

Introduction

Section snippets

Lipoprotein lipase deficiency (LPLD) and pancreatitis

Conventional clinical management of LPLD

Alipogene tiparvovec

Alipogene tiparvovec is provided as a solution for intramuscular injection

Preclinical studies

Clinical development program

Additional studies and pooled data on the incidence of pancreatitis in LPLD

Risk assessment and ethical issues

Summary

Conflict of interest statement

Acknowledgements

Familial lipoprotein lipase deficiency, Apo C-II deficiency and hepatic lipase deficiency

Lipoprotein lipase: physiology, biochemistry, and molecular biology

Front Biosci

Primary lipoprotein-lipase-activity deficiency: clinical investigation of a French Canadian population

CMAJ

Chylomicronemia with low postheparin lipoprotein lipase levels in the setting of GPIHBP1 defects

Circ Cardiovasc Genet

Combination of circulating antilipoprotein lipase (Anti-LPL) antibody and heterozygous S172 fsX179 mutation of LPL gene leading to chronic hyperchylomicronemia

J Clin Endocrinol Metab

Dietary treatment and growth of hyperchylomicronemic children severely restricted in dietary fat

Am J Dis Child

The familial chylomicronemia syndrome

Endocrinol Metab Clin N Am

Clinical assessment of hyperlipidemic pancreatitis

Am J Gastroenterol

Chronic pancreatitis: diagnosis, classification, and new genetic developments

Gastroenterology

Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene

N Engl J Med

Acute pancreatitis

Lancet

Chronic pancreatitis: genetics and pathogenesis

Annu Rev Genomics Hum Genet

Clinical characterization of patients with idiopathic chronic pancreatitis and SPINK1 mutations

Scand J Gastroenterol

Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis

N Engl J Med

Genetic aspects of pancreatitis

Annu Rev Med

The pancreas misled: signals to pancreatitis

Pancreatology