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FDA批准首款基因疗法Luxturna上市，为遗传性失明者揭开黑幕

2017-12-22 04:31:42 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： 基因治疗Luxturna是在美国被批准的第一个基因治疗靶向一种通过在一种特殊基因所致突变疾病。2017年12月19日,美国食品和药品监管局今天批准基因治疗Luxturna(voretigene neparvovec-rzyl)，一种新基因治疗 ...

关键字：voretigeneneparvovec 商品名luxturna 基因治疗遗传性失明

基因治疗Luxturna是在美国被批准的第一个基因治疗靶向一种通过在一种特殊基因所致突变疾病。
2017年12月19日,美国食品和药品监管局今天批准基因治疗Luxturna(voretigene neparvovec-rzyl)，一种新基因治疗，治疗儿童和成年患者有一种遗传形式视力丧失可能导致失明。基因治疗是在美国第一个直接给予的基因治疗靶向在一个特殊基因中突变所致的一种疾病。
FDA长官Scott Gottlieb，M.D.说：“今天的批准标记另一个基因治疗的另一个其他第一个领域 — 两者在如何治疗作用和基因治疗超出癌症治疗至视力丧失的治疗 — 而这个里程碑增强在治疗一个宽广-范围的挑战性疾病这个突破性方法的潜力。几十年研究的积累已导致在今年批准对有严重和罕见疾病患者的三个基因治疗。我相信基因治疗将成为在治疗中的一个支柱，和可能是治愈我们的许多最具破坏性和棘手的疾病，” “我们是处于一个转折点当它成为这个新形式的治疗和在FDA，我们集中确定正确的政策网络利用这个科学的开放。下一年，我们将开始发行一套疾病专用指导文件关于特异性基因治疗产品的开发布置现代和更有效的参数 — 包括新临床措施 — 为评价和审评对不同的高度重视的疾病其平台正在靶向。”
基因治疗被批准为患者有被确证的双等位基因RPE65突变相关的视网膜营养不良的治疗，它导致视力丧失和在某些患者中可能致完全失明。
遗传性视网膜营养不良是一个宽广组的遗传性视网膜疾病是伴随进行性视力障碍和是被突变在任何一个超过220个不同基因之一引起。在美国双等位基因RPE65突变相关的视网膜营养不良影响约1,000至2,000 患者。双等位基因突变携带者有一个突变(不一定是相同突变) 在某个特殊基因的两个拷贝(一个目前的和一个父亲突变)。RPE65基因提供指导为制造一个酶(一个蛋白加速化学反应)对正常视力至关重要。在RPE65基因中突变导致减低或缺乏RPE65活性的水平，阻断视觉周期和导致受损的视力。有双等位基因RPE65突变相关的视网膜营养不良个体经受视力随时间进行性变坏。视力的这个丧失，往往在儿童或青春期时，最终进展至完全失明。
基因治疗作用通过输送RPE65基因的正常拷贝直接至视网膜细胞。然后这些视网膜细胞的该正常蛋白在视网膜中产生正常蛋白转化光至一个电信号恢复患者的丧失视力。基因治疗使用一个天然存在的腺相关病毒[adeno-associated virus]，它曽被用重组DNA技术修饰，如一个载体输送正常人RPE65基因至视网膜细胞已恢复视力。
FDA的生物制品评价和研究中心(CBER)主任M.D.，Ph.D. Peter Marks说： “基因治疗的批准进一步打开基因治疗的潜能的大门，”“有双等位基因RPE65突变相关的视网膜营养不良患者现有一个机会改进视力，在以前存在的希望很小。”
基因治疗应仅被给予至患者有活力的视网膜细胞当被治疗医生们测定。在各个眼用基因治疗治疗必须在分开天分别做手术操作间至少间隔6天。被一位在进行眼内手术经验的外科医生通过视网膜下注射给药。患者应被口服泼尼松的一个短疗程治疗已限制对基因治疗限制潜在免疫反应。
在一项临床开发计划确定基因治疗的安全性和疗效用总共41例患者年龄4和44岁间。所有参加者有被确证的双等位基因RPE65 突变。基因治疗的疗效主要证据为根据一个3期研究有31位参加者过测量从基线至一年变化在一位受试者的能力在各种照明水平上驾驶障碍赛道。接受基因治疗患者组证实显示与对照组比较，显著改善在他们的能力完成障碍赛在低亮水平。
来自用基因治疗最常见不良反应包括眼发红 (结膜充血)，白内障，增加眼压和视网膜撕裂。
FDA授权这项申请优先审评和突破性治疗指定。基因治疗还接受孤儿药物指定，它提供奖励帮助和鼓励对罕见疾病药物的开发。
承办单位正在接受一个罕见儿童疾病优先审评凭证在一个意向鼓励开发新药和生物制品为预防和治疗罕见儿童疾病计划下。一个凭证可以为一个不同产品，在晚些时候由赞助商兑换接受随后上市申请的优先审评。这是FDA自从计划开始以来发出的第十三个儿童疾病优先审评凭证。
为了进一步评价涉及用基因治疗被治疗患者长期安全性，制造商计划进行一个上市后观察性研究。
FDA授权基因治疗的批准给予Spark Therapeutics有限公司。
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm589467.htm
FDA Approves Spark Therapeutics’ LUXTURNA™ (voretigene neparvovec-rzyl), a One-time Gene Therapy for Patients with Confirmed Biallelic RPE65 Mutation-associated Retinal Dystrophy
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.
"Today's landmark approval of LUXTURNA is a moment decades in the making for the field of gene therapy, the inherited retinal disease (IRD) community, and most importantly, patients with biallelic RPE65 mutation associated retinal dystrophy who now have the option to seek treatment," said Jeffrey D. Marrazzo, chief executive officer at Spark Therapeutics. "This one-time gene therapy for an inherited disease represents a first-of-its-kind breakthrough that may lay the groundwork for the development of gene therapies for other conditions that are not adequately addressed today. We offer our sincere gratitude to the patients and their families as well as the expert investigators who continue to participate in LUXTURNA's clinical development program."
"FDA approval of LUXTURNA represents a true paradigm shift for physicians caring for patients with hereditary retinal disease caused by biallelic RPE65 mutations, who up until now have had no pharmacologic treatment options," said Alex V. Levin, M.D., MHSc, pediatric ophthalmologist and chief of the Wills Eye Pediatric Ophthalmology and Ocular Genetics Service in Philadelphia. "Now is the time for patients who have hereditary retinal disease, but lack a confirmed genetic diagnosis, to undergo genetic testing to determine, where appropriate, if mutations in the RPE65 gene are responsible for their disease, and whether LUXTURNA may be an appropriate treatment option."
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. LUXTURNA is not recommended for patients younger than 12 months of age because the retina is still growing, which may affect how LUXTURNA works. LUXTURNA is administered by subretinal injection to each eye on separate days within a close interval, but no fewer than 6 days apart. Please see the Indication and Important Safety Information section below for more information regarding risks associated with LUXTURNA.
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.