The U.S. Food and Drug Administration today granted accelerated approval to Vyondys 53 injection to treat Duchenne muscular dystrophy patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. It is estimated that about 8 percent of patients with DMD have this mutation.
"The FDA recognizes the urgent need for new medical treatments for serious neurological disorders and we have a long-standing commitment to working with researchers, drug companies and patients to facilitate the development and approval of treatments for rare diseases. With today's accelerated approval, patients with Duchenne muscular dystrophy — a rare and devastating disease — who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype," said Billy Dunn, M.D., acting director of the Office of Neuroscience in the FDA's Center for Drug Evaluation and Research. "Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data and we look forward to learning more about the drug's clinical benefit from the ongoing confirmatory clinical trial."
DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.
People with DMD progressively lose the ability to perform activities independently and often require a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.
Vyondys 53 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally offer a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (i.e., how patients feel or function or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.
The accelerated approval of Vyondys 53 is based on the surrogate endpoint of an increase in dystrophin production in the skeletal muscle observed in some patients treated with the drug. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. A clinical benefit of the drug, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease and the lack of available therapy.
Vyondys 53 was evaluated in a two-part clinical study. The first part included 12 DMD patients, with eight patients receiving Vyondys 53 and four receiving placebo. The second part of the study was open-label, and included the 12 patients enrolled in part one of the study, and 13 additional patients who had not previously received the treatment. In the study, dystrophin levels increased, on average, from 0.10% of normal at baseline to 1.02% of normal after 48 weeks of treatment with the drug or longer.
As part of the accelerated approval process, the FDA is requiring the company to conduct a clinical trial to confirm the drug's clinical benefit. The ongoing study is designed to assess whether Vyondys 53 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 53 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.
The most common side effects reported by participants receiving Vyondys 53 in clinical studies were headache, fever (pyrexia), cough, vomiting, abdominal pain, cold symptoms (nasopharyngitis) and nausea. Hypersensitivity reactions, including rash, fever, itching, hives, skin irritation (dermatitis) and skin peeling (exfoliation), have occurred in patients who were treated with Vyondys 53.
Additionally, renal toxicity was observed in animals who received golodirsen. Although renal toxicity was not observed in the clinical studies with Vyondys 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Renal function should be monitored in patients taking Vyondys 53.
The FDA granted this application Fast Track and Priority Review designations. Vyondys 53 also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. In addition, the manufacturer received a rare pediatric disease priority review voucher. The FDA's rare pediatric disease priority review voucher program is intended to encourage development of new drugs and biologics to prevent and treat rare diseases in children.
Approval of Vyondys 53 was granted to Sarepta Therapeutics of Cambridge, Massachusetts.
National Institute of Neurological Disorders and Stroke: Muscular Dystrophy Information
FDA: Approved Drugs: Questions and Answers
FDA: New Drugs at FDA
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SOURCE U.S. Food and Drug Administration
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美国食品药品监督管理局（Food and Drug Administration）今天批准 Vyody53注射液加速治疗 Duchenne 肌营养不良患者，这些患者的营养不良基因经证实有突变，可以外显子53跳过。据估计，大约8%的 DMD 患者有这种突变。
“ FDA 认识到迫切需要新的治疗严重神经障碍的药物，我们长期致力于与研究人员、制药公司和患者合作，促进罕见疾病治疗的开发和批准。随着今天的加速批准，患有 Duchenne 肌营养不良症（一种罕见且具有破坏性的疾病）的患者，他们的肌营养不良基因经证实有突变，可供外显子53跳过，现在将有第一个治疗针对这种疾病亚型，” Billy Dunn 医学博士（M.D.）博士说。FDA 药物评价和研究中心神经科学办公室代理主任。“使用加速审批途径将使 Vyondi 53能够根据初步数据提供给患者，我们期待从正在进行的确认性临床试验中了解更多该药物的临床益处。”
DMD 是一种罕见的遗传性疾病，以进行性肌肉退化和虚弱为特征。这是最常见的类型肌肉萎缩症。DMD 是由缺乏肌营养不良引起的，这是一种有助于保持肌肉细胞完整的蛋白质。第一个症状通常出现在三到五岁之间，并随着时间的推移而恶化。这种疾病通常发生在没有已知的家族史的人，主要影响男孩，但在罕见的情况下，它可以影响女孩。全世界每3600名男性婴儿中就有一名患有 DMD 。
患有 DMD 的人逐渐丧失了独立进行活动的能力，并且通常在他们的早期青少年需要轮椅。随着疾病的发展，可能会出现危及生命的心脏和呼吸状况。患者通常在20或30多岁时就会患上这种疾病；然而，疾病的严重程度和预期寿命各不相同。
Vyondys 53的加速批准是基于在一些接受药物治疗的患者中观察到的骨骼肌中的营养不良蛋白产量增加的替代终点。FDA 的结论是，申请人提交的数据显示，在 DMD 患者中，营养不良蛋白的产量增加，这是合理的可能预测临床受益的， DMD 患者的营养不良蛋白基因已证实突变，可外显子53跳过。该药物的临床疗效，包括改善运动功能，尚未建立。在作出这一决定时， FDA 考虑了与药物有关的潜在风险、疾病的威胁生命和衰弱性质以及缺乏可用的治疗方法。
Vyondys 53在两部分临床研究中被评估。第一部分包括12例 DMD 患者，其中8例接受 Vyody53，4例接受安慰剂。研究的第二部分是开放标签，包括12名患者参加了第一部分的研究，另外13名患者以前没有接受治疗。在研究中，平均而言，在用药48周或更长时间后，营养不良蛋白水平从基线正常水平的0.10%上升到正常水平的1.02%。
作为加速审批程序的一部分， FDA 要求公司进行临床试验，以确认该药品的临床效益。正在进行的研究旨在评估 Vyody53是否改善 DMD 患者的运动功能，这些 DMD 患者的肌营养不良基因经证实有可能外显子53跳过的突变。如果试验未能验证临床疗效， FDA 可以启动撤回该药物批准的程序。
在临床研究中，接受 Vyody53治疗的患者最常见的副作用是头痛、发烧（发热）、咳嗽、呕吐、腹痛、感冒症状（鼻咽炎）和恶心。对 Vyondys 53治疗的患者发生了包括皮疹、发烧、瘙痒、荨麻疹、皮肤刺激（皮炎）和皮肤剥皮（脱皮）在内的过敏反应。
此外，在接受戈罗定治疗的动物中观察到了肾毒性。虽然在 Vyondis 53的临床研究中没有观察到肾脏毒性，但在给药一些反义寡核苷酸后观察到肾脏毒性，包括潜在的致命性肾小球肾炎。对服用 Vyondys 53的患者应监测肾功能。
FDA 批准了这一申请快速跟踪和优先审查指定。Vyondys 53还获得了孤儿药物的指定，该指定提供激励措施，以协助和鼓励开发罕见疾病的药物。此外，制造商还收到了一份罕见的儿科疾病优先审评凭证。FDA 的儿科罕见疾病优先审评凭证计划旨在鼓励开发新药和生物制剂，以预防和治疗儿童罕见疾病。
Vyondi 53的批准被授予马萨诸塞州剑桥的 Sarepta 疗法。
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美国食品药品监督管理局（Food and Drug Administration）