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Voretigene Neparvovec - Drugbank 5/18/2018 Voretigene Neparvovec - DrugBank Voretigene Neparvovec Targets (1) IDENTIFICATION Name Voretigene Neparvovec Accession Number DB13932 Type Biotech Groups Approved Biologic Classification Gene Therapies Other gene therapies 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] https://www.drugbank.ca/drugs/DB13932 1/9 5/18/2018 Voretigene Neparvovec - DrugBank Synonyms AAV2-hRPE65v2 Voretigene Neparvovec-rzyl Prescription Products Search MARKETING MARKETING NAME ↑↓ DOSAGE ↑↓ STRENGTH ↑↓ ROUTE ↑↓ LABELLER ↑↓ START ↑↓ END ↑↓ ↑↓ ↑↓ Luxturna Kit Spark 2017-12-19 Not applicable Therapeutics, Inc. Showing 1 to 1 of 1 entries ‹ › Categories Not Available UNII 2SPI046IKD CAS number 1646819-03-5 PHARMACOLOGY 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.[FDA 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 https://www.drugbank.ca/drugs/DB13932 2/9 5/18/2018 Voretigene Neparvovec - DrugBank 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] Structured Indications Hereditary Retinal Dystrophy Pharmacodynamics Subretinal injection generates the transduction of retinal pigment epithelial cells, restoring the visual cycle.[FDA 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] A Retinoid isomerohydrolase gene replacement Human 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, [ b l] https://www.drugbank.ca/drugs/DB13932 3/9 5/18/2018 Voretigene Neparvovec - DrugBank spleen and liver. There was a very small amount found in lymph nodes.[FDA Label] Volume of distribution VN-rzyl was shown to be distributed in serum.[FDA 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.[FDA 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 le aer 4 hours.[5] Toxicity Toxicology studies have not been conducted. Affected organisms Humans and other mammals Pathways Not Available Pharmacogenomic Effects/ADRs Not Available INTERACTIONS https://www.drugbank.ca/drugs/DB13932 4/9 5/18/2018 Voretigene Neparvovec - DrugBank Drug Interactions Not Available Food Interactions Not Available 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] External Links Not Available FDA label Download (602 KB) MSDS https://www.drugbank.ca/drugs/DB13932 5/9 5/18/2018 Voretigene Neparvovec - DrugBank Download (73.7 KB) CLINICAL TRIALS Clinical Trials Search PHASE ↑↓ STATUS ↑↓ PURPOSE ↑↓ CONDITIONS ↑↓ COUNT ↑↓ 1 Active Not Treatment Leber Congenital Amaurosis (LCA) 1 Recruiting 1, 2 Active Not Treatment Leber Congenital Amaurosis (LCA) 1 Recruiting 3 Active Not Treatment Inherited Retinal Dystrophy Due to RPE65 1 Recruiting Mutations / Leber Congenital Amaurosis (LCA) Showing 1 to 3 of 3 entries ‹ › PHARMACOECONOMICS Manufacturers Not Available Packagers Not Available Dosage forms Search FORM ↑↓ ROUTE ↑↓ STRENGTH ↑↓ Kit Showing 1 to 1 of 1 entries ‹ › Prices Not Available https://www.drugbank.ca/drugs/DB13932 6/9 5/18/2018 Voretigene Neparvovec - DrugBank Patents Not Available PROPERTIES State Liquid Experimental Properties PROPERTY VALUE SOURCE melting point (°C) 72-90ºC Rayaprolu V. et al. J. Virol. vol. 87. no. 24. (2013) water solubility Soluble 'MSDS' TAXONOMY Classification Not classified TARGETS 1. Retinoid isomerohydrolase Kind Protein Organism Human 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- https://www.drugbank.ca/drugs/DB13932 7/9 5/18/2018 Voretigene Neparvovec - DrugBank 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).
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