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FDA批准新型基因疗法Luxturna 用于遗传性视力丧失患者治疗

2017-12-29 03:07:43 作者：新特药房来源：互联网浏览次数：0 文字大小：【大】【中】【小】

简介： 新型基因疗法LUXTURNA™（voretigene neparvovec-rzyl），一种用于确诊为双链体RPE65突变相关性视网膜营养不良的患者的一次性基因治疗 12月19日,美国食品和药物管理局今天批准了一种新的基因治疗方 ...

关键字：voretigene neparvovec-rzyl商标名LUXTURNA™ 新型基因疗法用于遗传性视力丧失治疗

新型基因疗法LUXTURNA™（voretigene neparvovec-rzyl），一种用于确诊为双链体RPE65突变相关性视网膜营养不良的患者的一次性基因治疗
   12月19日,美国食品和药物管理局今天批准了一种新的基因治疗方法Luxturna(voretigene neparvovec-rzyl)治疗遗传性弱视的儿童和青壮年患者，这种遗传性弱视在人类的成长后期会发展为失明。Luxturna是第一个在美国被批准的可直接用于临床的基因疗法，用于特定基因突变引起的疾病。
   今日的批准标志着基因疗法领域的另一个‘新起点’，该疗法不仅有着新的工作机理，还将基因疗法应用到了癌症之外，还可治疗视力丧失。该里程碑在治疗各式各样具有挑战性的疾病上加强了其突破性疗法的潜能。经过几十年的研究，今年有三种基因疗法被批准用于治疗严重罕见疾病的患者。“我相信基因疗法将成为治疗或是治愈许多最具破坏性的顽疾的支柱。”美国食品与药物管理局局长Scott Gottlieb,M.D.说道：“我们正于一个转折点，当美国食品与药物管理局在处理这种新型疗法时，我们的重点是建立更完善的政策以利用这种科学开放带来的成果。”明年，我们将开始发行一套有关于治疗特殊疾病的特定基因疗法的产品开发发面的更有效的现代化指导文件，包括新的临床测量报告，平台已锁定了不同高优先级疾病的基因治疗的评估和审查。
   Luxturna被批准用于治疗确诊为双等位基因RPE65突变所致的视网膜营养障碍而导致视力丧失的患者，部分患有此病的患者可能发展为完全性失明。
遗传性视网膜营养障碍是一种常见的遗传性视网膜疾病，可导致进行性视觉功能障碍，可由220多种不同基因中的任何一种突变引起。
   在美国，大约有1000到2000人受累于双等位基因RPE65突变导致的视网膜营养障碍，双等位基因突变携带者在特定基因该（基因来自于父母中的一方）的每一次复制中都可能发生突变(不一定是相同的突变)。RPE65基因发出产生酶(一种催化蛋白质)的指令，这种酶在维护正常视力中必不可少。RPE65基因的突变可使RPE65活性降低或缺失，导致视觉周期受阻，进而视力受损。
   随着时间的推移，患有双等位基因RPE65突变所致的视网膜营养障碍的患者的视力会逐渐衰退。最终，这种视力丧失通常会在儿童期或青春期发展成完全失明。
   Luxturna可直接在视网膜细胞上正常复制RPE65基因。随后，这些视网膜细胞可产生正常的蛋白质，在视网膜上将光转化电信号，从而恢复病人的视力。Luxturna使用一种自然产生的已通过DNA重组技术修改的病毒作为载体将正常的人类RPE65基因植入视网膜细胞以恢复视力。
“Luxturna的批准进一步打开了基因疗法潜力的大门，”美国食品药品监督管理局的生物制品评价与研究中心主任Peter Marks博士说。“在此之前，双等位基因RPE65突变所致的视网膜营养障碍几乎没有治疗手段，现在则有望（通过Luxturna）技术改善视力。”
   由治疗医师决定将Luxturna技术应用于存在有活性的视网膜细胞的病人。不可同时在两只眼睛上进行Luxturna治疗，至少需要间隔6天（再治疗另一只眼睛）。该视网膜下注射由外科医生在进行眼内手术时进行。患者应口服强的松进行短期治疗以预防Luxturna的潜在过敏反应。
   Luxturna治疗最常见的不良反应包括眼红(结膜充血)、白内障、眼压增高和视网裂孔。
   美国食品和药物管理局批准了这项应用可获得优先审查证和突破性疗法命名权。Luxturna还获得了罕见病药的称号，这极大的鼓舞了（科研人员）开发罕见疾病药物。
Luxturna治疗最常见的不良反应包括眼红(结膜充血)、白内障、眼压增高和视网裂孔。
   美国食品和药物管理局批准了这项应用可获得优先审查证和突破性疗法命名权。Luxturna还获得了罕见病药的称号，这极大的鼓舞了（科研人员）开发罕见疾病药物。
   在一项旨在鼓励开发新药和生物制剂以预防和治疗罕见儿科疾病的项目中，主办方正在申请一项罕见的儿科疾病优先审查证。主办方可在随后获得一张优先审查证，用于不同产品的后续营销申请。这是自该项目启动以来，美国食品和药物管理局发布的第13个罕见的儿科疾病优先审查证。
   为了进一步评估长期安全性，制造商准备进行接受了Luxturna治疗的患者的随访调查。
   美国食品和药物管理局通过了罕见病基因疗法公司Luxturna上市的申请。
LUXTURNA™(voretigene neparvovec-rzyl)
U.S. Food and Drug Administration (FDA) has approved LUXTURNA™ (voretigene neparvovec-rzyl), a one-time gene therapy product indicated for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. LUXTURNA should only be administered to patients with mutations on both copies of the RPE65 gene who have sufficient viable retinal cells as determined by their treating physicians.
LUXTURNA is the first FDA-approved gene therapy for a genetic disease, the first and only pharmacologic treatment for an inherited retinal disease (IRD) and the first adeno-associated virus (AAV) vector gene therapy approved in the U.S.
Dosage Forms & Strengths
suspension for subretinal injection
•0.5mL extractable volume per 2mL vial
•Supplied concentration (ie, 5x10^12vg/mL) requires a 1:10 dilution before administration
Retinal Dystrophy
Indicated for confirmed biallelic RPE65 mutation-associated retinal dystrophy
Dose per eye: 1.5 x 10^11 vector genomes (vg) by subretinal injection in a total volume of 0.3 mL
Give subretinal administration to each eye on separate days within a close interval, but at least 6 days apart
See also Administration
Systemic oral corticosteroids
•Start systemic oral corticosteroids equivalent to prednisone at 1 mg/kg/day (not to exceed 40 mg/day) for a total of 7 days
•Initiate corticosteroid dosing regimen 3 days before administration to each eye; then taper dose during the next 10 days
•Same corticosteroid dosing regimen applies for the administration of voretigene neparvovex-rzyl to the second eye
•Taper corticosteroids
◦If the corticosteroid taper following the first eye is not complete 3 days before the planned administration to the second eye, then the corticosteroid regimen for the second eye replaces the taper for the first eye
Dosage Forms & Strengthssuspension for subretinal injection
0.5mL extractable volume per 2mL vialSupplied concentration (ie, 5x10^12vg/mL) requires a 1:10 dilution before administrationRetinal DystrophyIndicated for confirmed biallelic RPE65 mutation-associated retinal dystrophy
<1 year: Safety and efficacy not established
>1 year
Dose per eye: 1.5 x 10^11 vector genomes (vg) by subretinal injection in a total volume of 0.3 mLGive subretinal administration to each eye on separate days within a close interval, but at least 6 days apartSee also AdministrationSystemic oral corticosteroids
Start systemic oral corticosteroids equivalent to prednisone at 1 mg/kg/day (not to exceed 40 mg/day) for a total of 7 days Initiate corticosteroid dosing regimen 3 days before administration to each eye; then taper dose during the next 10 daysSame corticosteroid dosing regimen applies for the administration of voretigene neparvovex-rzyl to the second eyeTaper corticosteroidsIf the corticosteroid taper following the first eye is not complete 3 days before the planned administration to the second eye, then the corticosteroid regimen for the second eye replaces the taper for the first eye
Safety and efficacy not established
Clinical studies did not include patients aged ≥65 years
Adverse Effects
>10%
Incidence based on by number of eyes treated
Cataract (19%)
Conjunctival hyperemia (11%)
1-10%
Incidence based on by number of eyes treated
Increased intraocular pressure (10%)
Retinal tear (5%)
Eye inflammation (5%)
Dellen (thinning of the corneal stroma) (4%)
Macular hole (4%)
Subretinal deposits (4%)
Maculopathy (wrinkling on the surface of the macula) (4%)
Eye irritation (2%)
Eye pain (2%)
Foveal thinning and loss of function (2%)
Endophthalmitis (1%)
Fovea dehiscence (separation of the retinal layers in the center of the macula) (1%)
Retinal hemorrhage (1%)
Warnings
Contraindications
None
Cautions
Endophthalmitis may occur following any intraocular surgical procedure or injection; monitor and advise any signs or symptoms of infection or inflammation without delay
Permanent decline in visual acuity may occur following subretinal injection; monitor for visual disturbances
Retinal abnormalities (eg, macular holes, foveal thinning, loss of foveal function, foveal dehiscence, retinal hemorrhage) may occur; monitor and manage retinal abnormalities appropriately; do not administer voretigene neparvovex-rzyl in the immediate vicinity of the fovea
During or following vitrectomy, retinal abnormalities (eg, retinal tears, epiretinal membrane, retinal detachment) may occur; monitor during and following 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
Avoid air travel, travel to high elevation or scuba diving until the air bubble formed following administration has completely dissipated from the eye; may take >1 week or more following injection for the air bubble to dissipate; changes in altitude while the air bubble is still present can result in irreversible vision loss
Subretinal injection of voretigene neparvovex-rzyl, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression
Pregnancy
Pregnancy
Well-controlled human and animal reproductive studies with voretigene neparvovex-rzyl have not been conducted in pregnant women
No nonclinical or clinical studies were performed to evaluate the effect of voretigene neparvovex-rzyl on fertility
Lactation
No information regarding the presence of voretigene neparvovex-rzyl in human milk, the effects on the breastfed infant, or the effects on milk production
Development and health benefits of breastfeeding should be considered along with the mother’s clinical need for voretigene neparvovex-rzyl and any potential adverse effects on the breastfed infant from voretigene neparvovex-rzyl
Pregnancy Categories
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Administration
Subretinal Preparation
Prepare voretigene neparvovex-rzyl within 4 hr of administration using sterile technique under aseptic conditions in a Class II vertical laminar flow biological safety cabinet (BSC)
Dilution
•Thaw 1 single-dose vial of voretigene neparvovex-rzyl and 2 vials of diluent at room temperature
•Mix thawed diluent vials by gently inverting them ~5 times
•Visually inspect diluent and voretigene neparvovex-rzyl single-dose vials for particulates, cloudiness, or discoloration; do not use the vial(s) if particulates are present; new vial(s) of diluent should be used
•Using the 3-mL syringe with 20G 1-inch needle, transfer 2.7 mL of diluent to 10-mL glass vial
•Mix contents of thawed voretigene neparvovex-rzyl single-dose vial by gently inverting ~5 times
•Draw 0.3 mL voretigene neparvovex-rzyl into a 1-mL sterile syringe with a 27G ½-inch sterile needle
•Transfer 0.3 mL of voretigene neparvovex-rzyl to glass vial containing 2.7 mL of diluent
•Gently invert the 10-mL glass vial approximately 5 time to mix contents
•Label the 10-mL glass vial containing the diluted voretigene neparvovex-rzyl as follows: ‘Diluted LUXTURNA’
Preparation
•To keep the syringes sterile, 2 operators are required for transfer of the contents of the 10-mL glass vial labeled ‘Diluted LUXTURNA’ into each of 2 sterile 1-mL syringes
•Primary operator withdraws 0.8 mL of the diluted voretigene neparvovex-rzyl into a sterile 1-mL syringe using a 27G ½-inch sterile needle while the secondary operator holds the 10-mL glass vial
•Prepare a total of two administration syringes
•Label the first syringe “Diluted LUXTURNA” and label the second syringe “Backup Diluted LUXTURNA” using the sterile skin marker
•The second syringe serves as a backup for the surgeon performing the subretinal administration procedure
•Discard the backup syringe after surgery if not used
•Visually inspect both syringes; if particulates, cloudiness, or discoloration are visible, do not use the syringe
•Place the syringes into the sterile plastic bag after visual inspection and seal the bag
•Place the sterile plastic bag with syringes containing diluted voretigene neparvovex-rzyl into an appropriate secondary container (eg, hard plastic cooler) for delivery to the surgical suite at room temperature
Subretinal Administration
For subretinal injection only
Items are required for administration
•Syringe containing diluted voretigene neparvovex-rzyl
•Subretinal injection cannula with a polyamide micro tip with an inner diameter of 41G
•Extension tube made of polyvinyl chloride <6 inch (15.2 cm) in length and with an inner diameter <1.4 mm
Subretinal injection
•Dilate eye and give adequate anesthesia to the patient
•Administer a topical broad-spectrum microbiocide to the conjunctiva, cornea, and eyelids prior to surgery
•Visually inspect voretigene neparvovex-rzyl prior to administration; if particulates, cloudiness, or discoloration are visible, do not use the product
•Connect the syringe containing the diluted voretigene neparvovex-rzyl to the extension tube and subretinal injection cannula
•Avoid excess priming volume; extension tube should not exceed 15.2 cm in length and 1.4 mm in inner diameter
•Inject drug slowly through extension tube and subretinal injection cannula to eliminate any air bubbles
•Confirm the volume of product available in the syringe for injection by aligning the plunger tip with the line that marks 0.3 mL
•After completing a vitrectomy, identify the intended site of administration (see prescribing information for further illustrated information)
•Recommended site of injection: Along the superior vascular arcade, >2 mm distal to the center of the fovea, avoiding direct contact with the retinal vasculature or with areas of pathologic features, such as dense atrophy or intraretinal pigment migration
•Inject drug slowly until an initial subretinal bleb is observed; then inject remaining volume slowly until the total 0.3 mL is delivered
•After completing the injection, remove subretinal injection cannula from the eye
•Following injection, discard all unused product
•Perform a fluid-air exchange, carefully avoiding fluid drainage near the retinotomy created for the subretinal injection
•Initiate supine head positioning immediately in the postoperative period
•Upon discharge, advise patients to rest in a supine position as much as possible for 24 hr
Storage
Drug and diluent: Store frozen at ≤-65°C
Following thaw of vials: Store at room temperature; further dilute and administer within 4 hr
Diluted drug: Store at room temperature just prior to injection procedure
Indication and Important Safety Information
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.
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.
Adverse Reactions
•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%).
Immunogenicity
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. 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.
Pediatric Use
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 the full U.S. Prescribing Information for LUXTURNA here.
Clinical Trial Overview of LUXTURNA™ (voretigene neparvovec-rzyl)
The safety and efficacy of LUXTURNA were assessed in one open-label, dose-exploration Phase 1 safety study (n=12) and one open-label, randomized, controlled Phase 3 efficacy and safety study (n=31) in pediatric and adult participants (range 4 to 44 years) with biallelic RPE65 mutation-associated retinal dystrophy and sufficient viable retinal cells.
Of the 31 participants enrolled in the Phase 3 study, 21 were randomized to receive subretinal injection of LUXTURNA and 10 were randomized to the control (non-intervention) group. One participant in the intervention group discontinued from the study prior to treatment and one participant in the control group withdrew consent and was discontinued from the study. All nine participants randomized to the control group elected to crossover and receive LUXTURNA after one year of observation. All participants in these studies continue to be followed for long-term safety and efficacy. LUXTURNA Phase 3 clinical trial data, including data from the intervention group of all randomized participants through the one-year time point has been previously reported in (The Lancet).
The efficacy of LUXTURNA in the Phase 3 study was established based on the multi-luminance mobility test (MLMT) score change from baseline to one year. MLMT was designed to measure changes in functional vision as assessed by the ability of a participant to navigate a course accurately and at a reasonable pace at seven different levels of illumination, ranging from 400 lux (corresponding to a brightly lit office) to one lux (corresponding to a moonless summer night). Each light level was assigned a score ranging from zero to six, with a higher score indicating that a participant could pass MLMT at a lower light level. A score of negative one was assigned to participants who could not pass MLMT at a light level of 400 lux. MLMT score change was defined as the difference between the score at baseline and the score at one year with a positive score change indicating that a participant was able to complete MLMT at a lower light level. Additional clinical outcomes included white light full-field light sensitivity threshold (FST) testing and visual acuity.
LUXTURNA Phase 3 clinical study results showed a statistically significant difference between the intervention group (n=21) and control participants (n=10) at one year in median bilateral MLMT score change (intervention minus control group difference of 2; p=0.001) and median first-treated eye MLMT score change (intervention minus control group difference of 2; p=0.003). After crossing over to receive LUXTURNA, participants in the control group showed a similar response to those in the intervention group. The median bilateral MLMT score change of two was observed for the intervention group at the 30-day timepoint. This change score has been sustained for at least three years for the original intervention group and at least two years in the crossover group in the Phase 3 clinical study. In addition, participants who received LUXTURNA showed a statistically significant improvement from baseline to one year in white light FST in the intervention group compared to the control group. The change in visual acuity from baseline to one year was not significantly different between the intervention and control participants.
The U.S. Prescribing Information for LUXTURNA includes the following Warnings and Precautions: endophthalmitis; permanent decline in visual acuity; retinal abnormalities; increased intraocular pressure; expansion of intraocular air bubbles; and cataract. The most common adverse reactions (incidence ≥ 5%) were conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), macular hole, subretinal deposits, eye inflammation, eye irritation, eye pain and maculopathy (wrinkling on the surface of the macula).
About RPE65 Mutation-associated Inherited Retinal Disease (IRD)
Inherited retinal diseases (also known as inherited retinal dystrophies) are a group of rare blinding conditions caused by one of more than 220 different genes, often disproportionally affecting children and young adults. Based on Spark Therapeutics' assessment of available epidemiology data, the prevalent population in the U.S., Europe and select additional markets in the Americas and Asia/Pacific is up to approximately 6,000 individuals, in total, with biallelic RPE65 mutations. It is estimated that between 1,000-2,000 people in the U.S. have vision loss due to these biallelic RPE65 mutations. In addition, an expected 10-20 new patients a year are born with RPE65 mutations in the U.S.
People living with IRD due to biallelic RPE65 gene mutations nearly all progress to complete blindness. They often experience night blindness (nyctalopia) due to decreased light sensitivity in childhood or early adulthood and involuntary back-and-forth eye movements (nystagmus). As the disease progresses, individuals may experience loss in their peripheral vision, developing tunnel vision, and eventually, they may lose their central vision as well, resulting in total blindness. Independent navigation becomes severely limited, and vision-dependent activities of daily living are impaired. There are currently no approved pharmacologic treatment options for IRD due to biallelic RPE65 gene mutations.
About Gene Therapy
Gene therapy is an approach to treat or prevent genetic disease by seeking to augment, replace or suppress one or more mutated genes with functional copies. It addresses the root cause of an inherited disease by enabling the body to produce a protein or proteins necessary to restore health or to stop making a harmful protein or proteins, with the potential of bringing back function in the diseased cells and/or slowing disease progression. To deliver the functional gene into the cell, a vector is used to transport the desired gene and is delivered either intravenously or injected into specific tissue. The goal is to enable, through the one-time administration of gene therapy, a lasting therapeutic effect.