Lessons Learned from the Clinical Development and Market Authorization of Glybera

Bryant, Laura; Christopher, Devin M.; Giles, April R.; Hinderer, Christian; Rodriguez, Jesse L.; Smith, Jenessa B.; Traxler, Elizabeth A.; Tycko, Josh; Wojno, Adam; Wilson, James M.

doi:10.1089/humc.2013.087

Cited by 165 publications

(137 citation statements)

References 20 publications

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“…Although immune suppressive treatments have been used safely over many years for organ transplantation, from a regulatory perspective it is important to ensure that its value with a given gene therapy product is established clearly during the development. For example, unless supported by data from nonclinical/clinical studies, routine use of immunotherapy for adeno-associated virus vector-based gene therapy may not be of value and is not encouraged (Bryant et al, 2013). A risk-based approach (European Medicines Agency, 2011) is needed to evaluate the potential for the development of immunogenicity and the resultant effect before planning the appropriate solution.…”

Section: Immunogenicitymentioning

confidence: 99%

Clinical Development of Gene Therapy Needs a Tailored Approach: A Regulatory Perspective from the European Union

Narayanan

Cossu

Galli

et al. 2014

Human Gene Therapy Clinical Development

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Section: Immunogenicitymentioning

confidence: 99%

Clinical Development of Gene Therapy Needs a Tailored Approach: A Regulatory Perspective from the European Union

Narayanan

Cossu

Galli

et al. 2014

Human Gene Therapy Clinical Development

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“…All subjects had confirmed mutations in the LPL gene, significantly reduced LPL activity (.20% of normal), detectable LPL mass in circulating post-heparin plasma ($5% of normal), and fasting plasma TGs of .10 mmol/L. 13 AMT-010-IM was administered in four subjects at 1 × 10 11 gc/kg, while the remaining subjects were given a higher dose of 3 × 10 11 gc/kg. The vector was administered as multiple injections into the quadriceps muscle.…”

Section: Clinical Development Of Glybera Phase I/ii (Ct-amt-010-01)mentioning

confidence: 99%

“…Additionally, data from long-term follow-up of the first two clinical studies indicated that incidence of pancreatitis may have been reduced in participants that received Glybera, although the numbers were too small to reach statistical significance. 13 A third trial was designed, CT-AMT-011-02, that primarily tested whether Glybera had long-lasting effects on postprandial chylomicron metabolism. 23 A dose of 1 × 10 12 gc/kg was chosen for coadministration with cyclosporine, mycophenolate mofetil, and a pre-dose bolus injection of methylprednisolone.…”

mentioning

confidence: 99%

An update on gene therapy for the treatment of lipoprotein lipase deficiency

Libby¹,

Wang²

2014

ODRR

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Lipoprotein lipase (LPL) is responsible for clearance of triglyceride-rich lipoproteins from the blood. Deficiency or defects in this enzyme result in profound hypertriglyceridemia and susceptibility to chronic, life-threatening pancreatitis. Management of LPL deficiency has traditionally been restricted to palliative care and strategies to reduce the risk of pancreatitis, including severe dietary restrictions of fat. Recently, the European Commission approved the first gene therapy treatment in the West to treat this rare disease. Alipogene tiparvovec (Glybera ® ) was granted marketing authorization in November 2012 to treat LPL deficiency in a subset of patients that are at increased risk for pancreatitis. Designed as a one-time treatment, the drug uses adeno-associated virus (AAV1) delivery of transgenic LPL to muscle in patients lacking functional enzyme. Although statistically significant reduction of serum triglycerides was initially observed in trial subjects, this effect was found to be transient, with triglyceride levels eventually rebounding to basal levels by 26 weeks in all participants. Nevertheless, despite the return of triglycerides to pretreatment levels, alipogene tiparvovec was found to have a long-term impact on postprandial chylomicron metabolism by lowering the fraction of triglyceride found in this subset of lipoproteins. Furthermore, the drug led to a clinically significant reduction in the incidence of pancreatitis in LPL-deficient patients. The regulatory approval of alipogene tiparvovec was a historic process and serves as an example of the challenges that future orphan drugs will face.

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“…AAV vectors have been extensively studied in clinical trials, for example, for haemophilia B (Nathwani et al, 2011), heart disease ( Jessup et al, 2011), and congenital blindness (Bennett et al, 2012). In addition, the first EU-licensed gene therapy product, Glybera, for the treatment of a rare metabolic disease (Bryant et al, 2013) is based on AAV, exemplifying a great promise for AAV vectors in gene therapy. Despite many advances in AAV vector design, barriers such as a pre-existing immune response have necessitated the administration of high titer AAV and, in many cases, a combined administration of an immune-suppressant to achieve clinical efficacy, presenting a significant challenge in AAV production and considerable safety implications in the clinical use of AAV vectors.…”

Section: Introductionmentioning

confidence: 99%

“…HUMAN GENE THERAPY 25:929-941 (November 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089DOI: 10. /hum.2014 as in the case of the first marketed product Glybera, which is required to be administered to patients as a dose of 3x10 12 vg/ kg via 40 or 60 multiple injections (Bryant et al, 2013). To improve AAV production, in terms of high-titer and better quality production of AAV vectors, significant efforts have been made, including the generation of partial stable producer cell lines with the integration of AAV plasmids to allow a two-step and controlled production process (Gao et al, 1998;Martin et al, 2013) and the reduction of immunoreactivity of AAV vectors (Wu, 2001;Kaludov et al, 2002;Davidoff et al, 2004;Qu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Establishment of a Novel Cell Line for the Enhanced Production of Recombinant Adeno-Associated Virus Vectors for Gene Therapy

et al. 2014

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Adeno-associated viral (AAV) vectors show great promise because of their excellent safety profile; however, preexisting immune responses have necessitated the administration of high titer AAV, posing a significant challenge to the advancement of gene therapy involving AAV vectors. Recombinant AAV vectors contain minimum viral proteins necessary for their assembly and gene delivery functions. During the process of AAV assembly and production, AAV vectors acquire, inherently and submissively, various cellular proteins, but the identity of these proteins is poorly characterized. We reason that by identifying host cell proteins inherently associated with AAV vectors we may better understand the contribution of cellular components to AAV vector assembly and, ultimately, may improve the production of AAV vectors for gene therapy. In this study, three serotypes of recombinant AAV, namely AAV2, AAV5, and AAV8, were investigated. We used liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methods to identify protein composition in purified AAV vectors, confirmed protein identities using western blotting, and explored the potential function of selected proteins in AAV vector production using small hairpin (shRNA) methods. Using LC-MS/MS, we identified 44 AAVassociated cellular proteins including Y-box binding protein (YB1). We showed for the first time that the establishment of a novel producer cell line by introducing an shRNA sequence down-regulating YB1 resulted in up to 45-and 9-fold increase in physical vector genome titers of AAV2 and AAV8, respectively, and up to 7-fold increase in AAV2 transduction vector genome titers. Our results revealed that YB1 gene knockdown promoted AAV2 rep expression and vector DNA production and reduced the number of empty particles in AAV2 products, suggesting that YB1 plays an important role in AAV vector assembly by competition with adenovirus E2A and AAV capsid proteins for binding to the inverted terminal repeat (ITR) sequence. The significance and implications of our findings in future improvement of AAV production are discussed.

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Lessons Learned from the Clinical Development and Market Authorization of Glybera

Cited by 165 publications

References 20 publications

Clinical Development of Gene Therapy Needs a Tailored Approach: A Regulatory Perspective from the European Union

Clinical Development of Gene Therapy Needs a Tailored Approach: A Regulatory Perspective from the European Union

An update on gene therapy for the treatment of lipoprotein lipase deficiency

Establishment of a Novel Cell Line for the Enhanced Production of Recombinant Adeno-Associated Virus Vectors for Gene Therapy

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