Voretigene neparvovec

Identification

Name
Voretigene neparvovec
Accession Number
DB13932
Description

Voretigene Neparvovec-rzyl (VN-rzyl) is an adeno-associated virus vector-based gene therapy.6 An adeno-associated virus is a small virus that infects humans and other primates. It is not pathogenic and it causes a very mild immune response. This type of virus is vastly used as vectors for gene therapy because they can infect dividing and quiescent cell integrating just the carried genes into the host genome without fully integrating into the genome.1 An advantage of this adeno-associated virus is the high predictability, unlike retrovirus, as they associate with a specific region of the human cellular genome localized in the chromosome 19. When used in genetic therapy, this virus is modified for the elimination of its negligible integrative capacity by the removal of rep and cap and the insertion of the desired gene with its promoter between the inverted terminal repeats.2 VN-rzyl was developed by Spark Therapeutics Inc. and FDA approved on December 19, 2017.7

Type
Biotech
Groups
Approved
Biologic Classification
Gene Therapies
Other gene therapies
Synonyms
  • AAV2-hRPE65v2
  • VN-rzyl
  • Voretigene neparvovec
  • Voretigene Neparvovec-rzyl

Pharmacology

Pharmacology
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Indication

VN-rzyl is indicated for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The administration of VN-rzyl is conditioned to the physician determination of the presence of viable retinal cells.Label The RPE65 represents the LCA2 form of the Leber's congenital amaurosis (LCA). LCA is a group of inherited conditionts that involves retinal degeneration and severe vision loss in early childhood leading to total blindness by 30-40 years old. The LCA2 form is associated with a mutation that interferes with the isomerohydrolase activity of the retinal pigment epithelium. The isomerohydrolase activity transforms the trans-retinyl esters to 11-cis-retinal which is the natural ligand and chromophore of the opsins of rod and cones photoreceptors. In the presence of RPE65 mutations, the opsins cannot capture light or transduce it into electrical responses to initiate vision.3

Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Subretinal injection generates the transduction of retinal pigment epithelial cells, restoring the visual cycle.Label In clinical trials, there was a significant increase in the mean bilateral multi-luminance mobility testing scores with a shown maximum possible improvement.4 The eyes receiving the treatment presented also a more effective drive in pupillary response even 3 times greater than the baseline. There was also a significant reduction of nystagmus.3 The improved vision was determined by the ability of the treated patients to cross an obstacle course at various light levels which showed a significant amelioration.7

Mechanism of action

VN-rzyl is designed for the delivery, in the cells of the retina, of a normal copy of the gene encoding for the human retinal pigment epithelial protein whose molecular weight is 65 kDa. The delivery of this gene will allow the production of the RPE65 protein re-establishing the visual cycle and restoring the visual function.3 The adeno-associated viral vectors (AAVV) presents two open reading frames encoding for its replication (rep) and capsid (cap). It contains as well a zone with inverted terminal repeats which are required for the replication and packing of the viral genome. The replication of the AAVV requires the presence of a co-infector such as adenovirus or herpesvirus. Thus, without this co-infector, AAVV stays latent with its viral genome in the infected cell. The AAVV construct will contain the transgene in the inverted terminal repeats and it will replace the rep and cap sequences. The final AAVV will enter the cell nucleus and persist in different states. The first one involves the conversion of the AAVV genome into double-stranded circular episome which will later become a concatamer and provide a long-term transgene expression, particularly in non-dividing cells. The second option, presented in 0.1% of AAVV, is the integration at non-homologous sites of the host genome as single-copy proviruses or concatamers. In both options, there will be the presence of transgene expression.1

TargetActionsOrganism
ARetinoid isomerohydrolase
gene replacement
Humans
Absorption

In preclinical studies, it was found a high level of vector DNA sequences in intraocular fluids as anterior chamber fluid or vitreous. Lower levels were detected in optic nerves, optic chiasm, spleen and liver. There was a very small amount found in lymph nodes.Label

Volume of distribution

VN-rzyl was shown to be distributed in serum.Label

Protein binding
Not Available
Metabolism
Not Available
Route of elimination

VN-rzyl is eliminated transiently and at low levels in tears of both, the injected (45%) and non-injected eye (7%) until day 3 post-injection. Most of the drug elimination by the tears happend during day 1 post-injection.Label

Half-life

Based on the pharmacokinetic preclinical studies performed with VN-rzyl and previous studies with different AAVV, it is possible to determine that the half-life of VN-rzyl is approximately 1.7 hours.5

Clearance

According to the kinetics of AAVV obtained in preclinical trials, VN-rzyl will present a rapid clearance with less than 3% of the administered dose left after 4 hours.5

Adverse Effects
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Toxicity

Toxicology studies have not been conducted.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions
Not Available

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Luxturna5000000000000 vg/mlNovartis Europharm Limited2020-12-16Not applicableEU flag
LuxturnaSolution0.05 mg/1IntraocularSpark Therapeutics, Inc.2017-12-19Not applicableUS flag
LuxturnaSolution5000000000000 vgIntraocularNovartisNot applicableNot applicableCanada flag

Categories

ATC Codes
S01XA27 — Voretigene neparvovec
Drug Categories
Classification
Not classified

Chemical Identifiers

UNII
2SPI046IKD
CAS number
1646819-03-5

References

General References
  1. Deyle DR, Russell DW: Adeno-associated virus vector integration. Curr Opin Mol Ther. 2009 Aug;11(4):442-7. [PubMed:19649989]
  2. Kotin RM, Siniscalco M, Samulski RJ, Zhu XD, Hunter L, Laughlin CA, McLaughlin S, Muzyczka N, Rocchi M, Berns KI: Site-specific integration by adeno-associated virus. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2211-5. [PubMed:2156265]
  3. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J: Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2240-8. doi: 10.1056/NEJMoa0802315. Epub 2008 Apr 27. [PubMed:18441370]
  4. Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, Wittes J, Pappas J, Elci O, McCague S, Cross D, Marshall KA, Walshire J, Kehoe TL, Reichert H, Davis M, Raffini L, George LA, Hudson FP, Dingfield L, Zhu X, Haller JA, Sohn EH, Mahajan VB, Pfeifer W, Weckmann M, Johnson C, Gewaily D, Drack A, Stone E, Wachtel K, Simonelli F, Leroy BP, Wright JF, High KA, Maguire AM: Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017 Aug 26;390(10097):849-860. doi: 10.1016/S0140-6736(17)31868-8. Epub 2017 Jul 14. [PubMed:28712537]
  5. van Gestel MA, Boender AJ, de Vrind VA, Garner KM, Luijendijk MC, Adan RA: Recombinant adeno-associated virus: efficient transduction of the rat VMH and clearance from blood. PLoS One. 2014 May 23;9(5):e97639. doi: 10.1371/journal.pone.0097639. eCollection 2014. [PubMed:24858547]
  6. FDA Vaccines, Blood and Biologics [Link]
  7. FDA News and Events [Link]
RxNav
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Wikipedia
Voretigene_neparvovec
FDA label
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MSDS
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentInherited Retinal Dystrophy Due to RPE65 Mutations / Leber Congenital Amaurosis (LCA)1
1CompletedTreatmentLeber Congenital Amaurosis (LCA)1
1, 2Active Not RecruitingTreatmentLeber Congenital Amaurosis (LCA)1
Not AvailableActive Not RecruitingNot AvailableConfirmed Biallelic RPE65 Mutation-associated Retinal Dystrophy1
Not AvailableActive Not RecruitingNot AvailableInherited Retinal Dystrophy Due to RPE65 Mutations1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionIntraocular
SolutionIntraocular0.05 mg/1
SolutionIntraocular5000000000000 vg
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)72-90ºCRayaprolu V. et al. J. Virol. vol. 87. no. 24. (2013)
water solubilitySoluble 'MSDS'

Targets

Drugtargets
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Gene replacement
General Function
Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins. Catalyzes the cleavage and isomerization of all-trans-retinyl fatty acid esters to 11-cis-retinol which is further oxidized by 11-cis retinol dehydrogenase to 11-cis-retinal for use as visual chromophore (PubMed:16116091). Essential for the production of 11-cis retinal for both rod and cone photoreceptors (PubMed:17848510). Also capable of catalyzing the isomerization of lutein to meso-zeaxanthin an eye-specific carotenoid (PubMed:28874556). The soluble form binds vitamin A (all-trans-retinol), making it available for LRAT processing to all-trans-retinyl ester. The membrane form, palmitoylated by LRAT, binds all-trans-retinyl esters, making them available for IMH (isomerohydrolase) processing to all-cis-retinol. The soluble form is regenerated by transferring its palmitoyl groups onto 11-cis-retinol, a reaction catalyzed by LRAT (By similarity).
Specific Function
All-trans-retinyl-ester hydrolase, 11-cis retinol forming activity
Gene Name
RPE65
Uniprot ID
Q16518
Uniprot Name
Retinoid isomerohydrolase
Molecular Weight
60947.08 Da
References
  1. Deyle DR, Russell DW: Adeno-associated virus vector integration. Curr Opin Mol Ther. 2009 Aug;11(4):442-7. [PubMed:19649989]
  2. Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett J: Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2240-8. doi: 10.1056/NEJMoa0802315. Epub 2008 Apr 27. [PubMed:18441370]

Drug created on December 19, 2017 23:18 / Updated on February 21, 2021 18:54