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Libmeldy是一种用于治疗患有异色性白细胞营养不良（MLD）的儿童的药物。 MLD是一种罕见的遗传性疾病，其中制造一种叫做芳基硫酸酯酶A（ARSA）的酶所需的基因发生改变（突变），该酶会分解称为硫酸盐的物质。结果，硫化物积聚并损害神经系统和其他器官，引起诸如行走困难，逐渐的智力退化和最终死亡等症状。

 

Libmeldy用于ARSA基因突变的MLD儿童。它给

 

尚未出现症状的晚期婴儿或青少年早期疾病的患者；

那些有初期症状但仍可以独立行走且尚未发展为智力衰退的早期MLD的人。

Libmeldy是一种称为“基因疗法”的高级治疗药物。这种药物通过将基因传递到体内而起作用。 Libmeldy中的活性物质是干细胞（CD34 +细胞），其来源于患者自身的骨髓或血液，经过修饰以包含该基因的副本以形成ARSA，并可以分裂产生其他种类的血细胞。

 

MLD很罕见，2007年4月13日，利比梅利被指定为“罕见病药物”（一种用于罕见病的药物）。

 

 

Libmeldy如何使用？

Libmeldy只能通过处方获得，并且只能在专业的移植中心进行治疗。

 

为了制备Libmeldy，需要从患者的骨髓或血液中收集含有干细胞的样本。通过包括制造ARSA的基因的副本，将这些修饰为Libmeldy。

 

Libmeldy只能给予使用细胞制造药物的患者。这是一种单次治疗，以静脉输注（滴注）的方式进行，剂量取决于患者的体重。治疗前几天，另一种药物白消安被称为所谓的调理疗法，以清除现有的骨髓细胞，以便可以用Libmeldy中的修饰细胞替代它们。治疗前还给患者服用其他药物，以减少反应的风险。

 

有关使用Libmeldy的更多信息，请参阅包装传单或与您的医生或药剂师联系。

 

 

Libmeldy如何工作？

为了制造Libmeldy，必须从血液或骨髓中提取CD34 +细胞（可以制造白细胞的细胞）。使用一种叫做慢病毒的病毒将一种允许它们产生ARSA的基因插入CD34 +细胞，这种病毒已经过基因改造，因此可以将ARSA基因携带到细胞中，而不会引起人类的病毒性疾病。

 

一旦被送回患者的静脉，Libmeldy就会在血液中被输送到骨髓，在那里CD34 +细胞开始生长并产生可以产生正常ARSA的正常白细胞。这些白细胞在体内传播并产生ARSA，有助于分解周围细胞中的硫化物，从而控制疾病的症状。预期效果将是持久的。

 

 

研究中显示了利伯梅利有什么好处？

一项涉及20名婴儿晚期或少年早期MLD的儿童的主要研究显示了Libmeldy治疗MLD的益处。在治疗后3个月内，所有儿童的ARSA活性均升高至健康儿童之上或之上的水平。两年后，晚期MLD组的总体运动功能总体评分（该值在0到100之间，用于衡量发育中的孩子进行正常运动（例如爬行，站立和行走）的能力）为72.5，而记录中为7.4相似的未治疗儿童。同样，在患有早期MLD的儿童中，使用Libmeldy治疗2年的平均评分为76.5，而之前未治疗的病例的平均评分为36.3。对于尚未出现症状并且似乎无法再单独行走或已发展为智力衰退的孩子，收益最大。

 

有证据表明，长达8年的随访持续受益。

 

 

与Libmeldy相关的风险是什么？

Libmeldy的最常见副作用（可能影响超过十分之一的人）是针对ARSA的抗体的开发，尽管这似乎并没有影响Libmeldy的功效。白消安的调理治疗的结果是，白细胞计数低，有时发烧（感染的迹象），代谢性酸中毒（体内酸水平失衡），口腔炎（口发炎），呕吐，肝肿大（肝脏肿大），静脉阻塞性肝病（当肝的血管阻塞导致肝损害时）和女孩的卵巢衰竭也很常见。

 

有关Libmeldy副作用的完整列表，请参阅包装手册。

 

既往曾接受过涉及血液干细胞的基因治疗的患者，或不能获得制备其生产或接受利勃梅利所需药物的患者，不得使用利勃梅利。有关限制的完整列表，请参见包装手册。

 

 

为什么Libmeldy在欧盟获得授权？

Libmeldy对尚未出现症状的MLD患者的益处显而易见，并且在研究期间，患者的进展与健康受试者相似。在已经出现症状的早期MLD中，获益较少，而且变化较大，因此该组患者的使用仅限于仍能行走且未出现精神功能下降的患者。

 

尽管利比梅利的获益持续了数年，但尚不清楚它是否会终身存在，因此需要延长随访时间。由于MLD是一种罕见疾病，因此研究规模很小，并且关于副作用的可用数据量有限，并且还需要长期随访。然而，迄今为止观察到的副作用与这种治疗所预期的一致。考虑到病情的严重性和缺乏现有的治疗方法，欧洲药品管理局认为利比梅利的好处大于其风险，可以授权在欧盟使用。

 

 

正在采取什么措施来确保安全有效地使用Libmeldy？

销售Libmeldy的公司将进行长期研究，以提供有关该药物的益处和安全性的进一步信息，并将采取步骤以确保符合治疗条件的患者可以快速生产出这种药物，以便对其进行治疗在症状开始或进展之前，尽早。此外，该公司还将为医护专业人员和患者或其护理人员提供有关如何使用和监测Libmeldy的教育材料，并提供有关患者治疗的患者警报卡，以在接受医疗服务时显示给患者。

 

产品特性摘要和包装手册中还包括医疗专业人员和患者应遵循的有关安全有效使用Libmeldy的建议和预防措施。

 

对于所有药物，Libmeldy的使用数据都受到持续监控。对Libmeldy报告的副作用进行了仔细评估，并采取了任何必要的措施来保护患者。

 

 

有关利伯梅尔迪的其他信息

Libmeldy已获得2020年12月17日在整个欧盟范围内有效的营销许可。

Autologous CD34+ cells encoding ARSA gene

Overview

Libmeldy is a medicine used to treat children with metachromatic leukodystrophy (MLD). MLD is a rare inherited disorder in which there is a change (mutation) in a gene needed to make an enzyme called arylsulfatase A (ARSA), which breaks down substances called sulfatides. As a result, sulfatides build up and damage the nervous system and other organs, causing symptoms such as walking difficulties, gradual mental deterioration and eventual death.

Libmeldy is used in children with MLD who have mutations in the ARSA gene. It is given to

those with late infantile or early juvenile forms of the disease who have not yet developed symptoms;those with early juvenile MLD who have initial symptoms but can still walk independently and have not yet developed mental deterioration.

Libmeldy is a type of advanced therapy medicine called a ‘gene therapy’. This type of medicine works by delivering genes into the body. The active substance in Libmeldy is stem cells, (CD34+ cells), derived from the patient’s own bone marrow or blood, that have been modified to contain a copy of the gene to make ARSA and can divide to produce other sorts of blood cells.

MLD is rare, and Libmeldy was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 13 April 2007.

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How is Libmeldy used?

Libmeldy can only be obtained with a prescription and treatment should only be given in a specialist transplant centre.

To prepare Libmeldy, a sample containing stem cells is collected either from the patient’s bone marrow or blood. These are modified to make Libmeldy by including a copy of the gene to make ARSA.

Libmeldy can only be given to the patient whose cells were used to make the medicine. It is a single treatment, given as an infusion (drip) into a vein, and the dose depends on the patient’s weight. A few days before treatment another medicine, busulfan, is given as a so-called conditioning treatment, to clear out existing bone marrow cells so they can be replaced with the modified cells in Libmeldy. Patients are also given other medicines before treatment to reduce the risk of reactions.

For more information about using Libmeldy, see the package leaflet or contact your doctor or pharmacist.

How does Libmeldy work?

To make Libmeldy, the CD34+ cells (cells that can make white blood cells) are extracted from the blood or bone marrow. A gene allowing them to make ARSA is inserted into the CD34+ cells using a type of virus called a lentivirus, which has been altered genetically so that it can carry the ARSA gene into cells and does not cause viral disease in humans.

Once given back into the patient’s vein, Libmeldy is transported in the bloodstream to the bone marrow where the CD34+ cells start to grow and make normal white blood cells that can produce working ARSA. These white blood cells spread through the body and produce ARSA, helping to break down sulfatides in the surrounding cells, and so controlling symptoms of the disease. The effects are expected to be long-lasting.

What benefits of Libmeldy have been shown in studies?

The benefits of Libmeldy in treating MLD were shown in a main study involving 20 children with late infantile or early juvenile MLD. ARSA activity increased in all the children to levels above or within the range for healthy children within 3 months of treatment. After 2 years, the overall Gross Motor Function Measure score (a value between 0 and 100 measuring a developing child’s ability to make normal movements such as crawling, standing and walking) was 72.5 in the group with late infantile MLD, compared to 7.4 in records of similar untreated children. Similarly, in children with early juvenile MLD, the average score 2 years after treatment with Libmeldy was 76.5, whereas that in previous untreated cases was 36.3. Benefit was greatest in children who had not yet developed symptoms and seemed to be lost in those who could no longer walk independently or had developed mental deterioration.

There was evidence of continuing benefit on follow-up for up to 8 years.

What are the risks associated with Libmeldy?

The most common side effect with Libmeldy (which may affect more than 1 in 10 people) is development of antibodies to ARSA, although this does not seem to affect how well Libmeldy works. As a result of the conditioning treatment with busulfan, low white cell counts, sometimes with fever (a sign of infection), metabolic acidosis (imbalance in the body’s acid levels), stomatitis (mouth inflammation), vomiting, hepatomegaly (enlarged liver), veno-occlusive liver disease (when blood vessels to the liver become blocked causing liver damage) and ovarian failure in girls are also very common.

For the full list of side effects of Libmeldy, see the package leaflet.

Libmeldy must not be used in patients who have had previous gene therapy involving blood stem cells, or in those who cannot be given the medicines needed to prepare them for producing or receiving Libmeldy. For the full list of restrictions, see the package leaflet.

Why is Libmeldy authorised in the EU?

The benefits of Libmeldy in patients with MLD who had not yet developed symptoms were clear, and during the study period patients maintained similar progress to healthy subjects. Benefit was less marked and more variable in those with early juvenile MLD who already have symptoms, so use in this group was restricted to those who can still walk and have not developed decline in mental function.

Although benefit with Libmeldy lasted several years it is not yet clear whether it will persist life-long, and extended follow-up is needed. Because MLD is a rare disease, the studies are necessarily small and the amount of data available on side effects is limited, and will also need long-term follow-up; however, side effects seen to date were in line with those expected for this type of treatment. Given the seriousness of the condition and the lack of existing treatments, the European Medicines Agency decided that Libmeldy’s benefits are greater than its risks and it can be authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of Libmeldy?

The company that markets Libmeldy will carry out a long-term study to provide further information on the benefits and safety of the medicine, and will take steps to ensure that patients who qualify for the treatment can have the medicine produced quickly so they can be treated as early as possible, before symptoms start or progress. In addition, the company will provide educational materials for healthcare professionals and patients or their carers on how Libmeldy is to be used and monitored, and a patient alert card about their treatment for patients to show when receiving healthcare.

Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Libmeldy have also been included in the summary of product characteristics and the package leaflet.

As for all medicines, data on the use of Libmeldy are continuously monitored. Side effects reported with Libmeldy are carefully evaluated and any necessary action taken to protect patients.

Other information about Libmeldy

Libmeldy received a marketing authorisation valid throughout the EU on 17 December 2020.