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Voretigene neparvovec , ボレチジーンネパルボベック;
DNA (synthetic adeno-associated virus 2 vector AAV2-hRPE65v2)
2017/12/19, FDA Luxturna, SPARK THERAPEUTICS
Vision loss treatment, Retinal dystrophy
2SPI046IKD (UNII code)
|melting point (°C)||72-90ºC||Rayaprolu V. et al. J. Virol. vol. 87. no. 24. (2013)|
Proper Name: voretigene neparvovec-rzyl
Trade Name: LUXTURNA
Manufacturer: Spark Therapeutics, Inc.
- Is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients must have viable retinal cells as determined by the treating physician(s).
- Package Insert – LUXTURNA (PDF – 602KB)
- Demographic Subgroup Information – voretigene neparvovec [LUXTURNA] (PDF – 2.7MB)
Refer to Section 1.1 of the clinical reviewer memo for information about participation in the clinical trials and any analysis of demographic subgroup outcomes that is notable.
Voretigene neparvovec (Luxturna) is a novel gene therapy for the treatment of Leber’s congenital amaurosis. It was developed by Spark Therapeutics and Children’s Hospital of Philadelphia. It is the first in vivo gene therapy approved by the FDA.
Leber’s congenital amaurosis, or biallelic RPE65-mediated inherited retinal disease, is an inherited disorder causing progressive blindness. Voretigene is the first treatment available for this condition. The gene therapy is not a cure for the condition, but substantially improves vision in those treated. It is given as an subretinal injection.
It was developed by collaboration between the University of Pennsylvania, Yale University, the University of Florida and Cornell University. In 2018, the product was launched in the U.S. by Spark Therapeutics for the treatment of children and adult patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The same year, Spark Therapeutics received approval for the product in the E.U. for the same indication.
Chemistry and production
Voretigene neparvovec is an AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence. The virus is grown in HEK 293 cells and purified for administration.
Married researchers Jean Bennett and Albert Maguire, among others, worked for decades on studies of congenital blindness, culminating in approval of a novel therapy, Luxturna.
It was granted orphan drug status for Leber congenital amaurosis and retinitis pigmentosa. A biologics license application was submitted to the FDA in July 2017 with Priority Review. Phase III clinical trial results were published in August 2017. On 12 October 2017, a key advisory panel to the Food and Drug Administration (FDA), composed of 16 experts, unanimously recommended approval of the treatment. The US FDA approved the drug on December 19, 2017. With the approval, Spark Therapeutics received a pediatric disease priority review voucher.
The first commercial sale of voretigene neparvovec — the first for any gene therapy product in the US — occurred in March 2018. The price of the treatment has been announced at $425,000 per eye.
LUXTURNA (voretigene neparvovec-rzyl) is an adeno-associated virus vector-based gene therapy indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy.
Patients must have viable retinal cells as determined by the treating physicians.
IMPORTANT SAFETY INFORMATION FOR LUXTURNA
Warnings and Precautions
Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering LUXTURNA, and monitor for and advise patients to report any signs or symptoms of infection or inflammation to permit early treatment of any infection.
Permanent decline in visual acuity may occur following subretinal injection of LUXTURNA. Monitor patients for visual disturbances.
Retinal abnormalities may occur during or following the subretinal injection of LUXTURNA, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer LUXTURNA in the immediate vicinity of the fovea. Retinal abnormalities may occur during or following vitrectomy, including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay.
Increased intraocular pressure may occur after subretinal injection of LUXTURNA. Monitor and manage intraocular pressure appropriately.
Expansion of intraocular air bubbles Instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination.
Cataract Subretinal injection of LUXTURNA, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.
In clinical studies, ocular adverse reactions occurred in 66% of study participants (57% of injected eyes), and may have been related to LUXTURNA, the subretinal injection procedure, the concomitant use of corticosteroids, or a combination of these procedures and products.
The most common adverse reactions (incidence ≥5% of study participants) were conjunctival hyperemia (22%), cataract (20%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma) (7%), macular hole (7%), subretinal deposits (7%), eye inflammation (5%), eye irritation (5%), eye pain (5%), and maculopathy (wrinkling on the surface of the macula) (5%).
Immune reactions and extra-ocular exposure to LUXTURNA in clinical studies were mild. No clinically significant cytotoxic T-cell response to either AAV2 or RPE65 has been observed.
In clinical studies, the interval between the subretinal injections into the two eyes ranged from 7 to 14 days and 1.7 to 4.6 years. Study participants received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye, which may have decreased the potential immune reaction to either AAV2 or RPE65.
Treatment with LUXTURNA is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and LUXTURNA would potentially be diluted or lost during the cell proliferation. The safety and efficacy of LUXTURNA have been established in pediatric patients. There were no significant differences in safety between the different age subgroups.
Please see US Full Prescribing Information for LUXTURNA.
1. LUXTURNA [package insert]. Philadelphia, PA: Spark Therapeutics, Inc; 2017. 2. Gupta PR, Huckfeldt RM. Gene therapy for inherited retinal degenerations: initial successes and future challenges. J Neural Eng. 2017;14(5):051002. 3. Kay C. Gene therapy: the new frontier for inherited retinal disease. Retina Specialist. March 2017. http://www.retina-specialist.com/CMSDocuments/2017/03/RS/rs0317I.pdf. Accessed November 14, 2017 4. Polinski NK, Gombash SE, Manfredsson FP, et al. Recombinant adeno-associated virus 2/5-mediated gene transfer is reduced in the aged rat midbrain. Neurobiol Aging. 2015;36(2):1110-1120. 5. Moore T. Restoring retinal function in a mouse model of hereditary blindness. PLoS Med. 2005;2(11):e399. 6. McBee JK, Van Hooser JP, Jang GF, Palczewski K. Isomerization of 11-cis-retinoids to all-trans-retinoids in vitro and in vivo. J Biol Chem. 2001;276(51):48483-48493. 7. Thomas CE, Ehrhardt A, Kay MA. Progress and problems with the use of viral vectors for gene therapy. Nat Rev Genet. 2003;4(5):346-358. 8. Trapani I, Puppo A, Auricchio A. Vector platforms for gene therapy of inherited retinopathies. Prog Retin Eye Res. 2014;43:108-128. 9. Russell S, Bennett J, Wellman JA, et al. 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;390(10097):849-860.
Progress in Retinal and Eye Research (2018), 63, 107-131
Lancet (2017), 390(10097), 849-860.
- ^ “Luxturna (voretigene neparvovec-rzyl) label” (PDF). FDA. December 2017. Retrieved 31 December 2017. (for label updates, see FDA index page)
- ^ “Spark’s gene therapy for blindness is racing to a historic date with the FDA”. Statnews.com. 9 October 2017. Retrieved 9 October 2017.
- ^ Clarke,Reuters, Toni. “Gene Therapy for Blindness Appears Initially Effective, Says U.S. FDA”. Scientific American. Retrieved 2017-10-12.
- ^ Jump up to:a b “First Gene Therapy For Inherited Disease Gets FDA Approval”. NPR.org. 19 Dec 2017.
- ^ Jump up to:a b “Press Release – Investors & Media – Spark Therapeutics”. Ir.sparktx.com. Retrieved 9 October 2017.
- ^ McGinley, Laurie (19 December 2017). “FDA approves first gene therapy for an inherited disease”. Washington Post.
- ^ Russell, Stephen; Bennett, Jean; Wellman, Jennifer A.; Chung, Daniel C.; Yu, Zi-Fan; Tillman, Amy; Wittes, Janet; Pappas, Julie; Elci, Okan; McCague, Sarah; Cross, Dominique; Marshall, Kathleen A.; Walshire, Jean; Kehoe, Taylor L.; Reichert, Hannah; Davis, Maria; Raffini, Leslie; George, Lindsey A.; Hudson, F Parker; Dingfield, Laura; Zhu, Xiaosong; Haller, Julia A.; Sohn, Elliott H.; Mahajan, Vinit B.; Pfeifer, Wanda; Weckmann, Michelle; Johnson, Chris; Gewaily, Dina; Drack, Arlene; et al. (2017). “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65 -mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial”. The Lancet. 390 (10097): 849–860. doi:10.1016/S0140-6736(17)31868-8. PMC 5726391. PMID 28712537.
- ^ “FDA approves Spark’s gene therapy for rare blindness pioneered at CHOP – Philly”. Philly.com. Retrieved 2018-03-24.
- ^ “Voretigene neparvovec – Spark Therapeutics – AdisInsight”. adisinsight.springer.com.
- ^ Ricki Lewis, PhD (October 13, 2017). “FDA Panel Backs Gene Therapy for Inherited Blindness”. Medscape.
- ^ Lee, Helena; Lotery, Andrew (2017). “Gene therapy for RPE65 -mediated inherited retinal dystrophy completes phase 3”. The Lancet. 390 (10097): 823–824. doi:10.1016/S0140-6736(17)31622-7. PMID 28712536.
- ^ “Landmark Therapy to Treat Blindness Gets One Step Closer to FDA Approval”. Bloomberg.com. 2017-10-12. Retrieved 2017-10-12.
- ^ “Spark grabs FDA nod for Luxturna, a breakthrough gene therapy likely bearing a pioneering price”. FiercePharma.
- ^ Jump up to:a b “The anxious launch of Luxturna, a gene therapy with a record sticker price”. STAT. 2018-03-21. Retrieved 2018-03-24.
- ^ Tirrell, Meg (3 January 2018). “A US drugmaker offers to cure rare blindness for $850,000”. CNBC. Retrieved 3 January 2018.
- Ledford, Heidi (2017). “FDA advisers back gene therapy for rare form of blindness”. Nature. 550 (7676): 314. doi:10.1038/nature.2017.22819. PMID 29052639.
- Wilson, James M. (2018). “Interview with Jean Bennett, MD, PhD”. Human Gene Therapy Clinical Development. 29 (1): 7–9. doi:10.1089/humc.2018.29032.int. PMID 29641279.
- Ameri, Hossein (2018). “Prospect of retinal gene therapy following commercialization of voretigene neparvovec-rzyl for retinal dystrophy mediated by RPE65 mutation”. Journal of Current Ophthalmology. 30 (1): 1–2. doi:10.1016/j.joco.2018.01.006. PMC 5859497. PMID 29564403.
- Russell, Stephen; Bennett, Jean; Maguire, Albert M.; High, Katherine A. (2018). “Voretigene neparvovec-rzyl for the treatment of biallelic RPE65 mutation–associated retinal dystrophy”. Expert Opinion on Orphan Drugs. 6 (8): 457–464. doi:10.1080/21678707.2018.1508340.
- Bakall, Benjamin; Hariprasad, Seenu M.; Klein, Kendra A. (2018). “Emerging Gene Therapy Treatments for Inherited Retinal Diseases”. Ophthalmic Surgery, Lasers and Imaging Retina. 49 (7): 472–478. doi:10.3928/23258160-20180628-02. PMID 30021033.
- “Drug and Device News”. P & T. 43 (2): 74–104. 2018. PMC 5768294. PMID 29386862.
|Vector||Adeno-associated virusserotype 2|
|Nucleic acid type||DNA|
//////////FDA 2017, Voretigene neparvovec , Voretigene neparvovec-rzyl, Luxturna, ボレチジーンネパルボベック, 1646819-03-5 , FDA Luxturna, SPARK THERAPEUTICS, Vision loss treatment, Retinal dystrophy., AAV2-hRPE65v2, LTW-888, SPK-RPE65, Orphan drug,