Leukodystrophy NOS

当地时间3月18日，美国食品药品监督管理局宣布批准Orchard Therapeutics公司研发的基因疗法Lenmeldy上市，用于治疗异染性脑白质营养不良儿童患者。定价为425万美元(约人民币3070万元)一剂，超过Hemgenix跃升为有史以来最昂贵的药物。人民日报健康客户端根据各企业公布信息统计，截至3月22日，FDA批准上市的5款全球最贵药物，均为基因疗法。涉及的适应症分别为易染性脑白质营养不良、A型血友病、B型血友病、杜氏肌营养不良以及脑性肾上腺脑白质营养不良。清华大学药学院创院院长、全球健康药物研发中心主任丁胜向人民日报健康客户端记者表示，“基因疗法定价不菲的原因有多重，定价策略需要综合考量研发投入、生产成本、潜在疗效和市场需求等多种因素。”据Orchard公司称，Lenmeldy是美国食品药品监督管理局批准的治疗早发型异染性脑白质营养不良儿童患者的唯一疗法。这种疾病是一种极其罕见、进展迅速、不可逆转且最终致命的神经代谢疾病，常见于6个月至2岁之间的婴儿，通常会剥夺患者行走、说话和生活的能力，大多数患者会在发病后五年内死亡。“一种基因治疗是指将外源正常基因通过基因转移技术导入靶细胞，以纠正或代偿基因缺陷和异常引起的疾病，最终达到治疗目的的一种生物治疗方法。跟普通药物相比，这一治疗方式的前期研发有很高门槛，治疗基因的设计、优化乃至载体选择都不容易，而基因疗法的链条非常长，选择何种载体、何种片段的治疗基因、基因治疗过程中采用何种技术，每一个环节都需要根据患者的情况进行设计以及质检，才能保证安全，这就导致有些品种的药品难以批量化生产，生产成本居高不下。”丁胜解释。丁胜表示，“基因治疗有望实现对单基因遗传病的彻底治愈，高定价有其合理性。提高产量，降低生产成本是目前基因疗法亟需突破的痛点难点，目前科学界已经在着手研发一套标准化的基因载体系统，有了标准化的基因载体系统之后，在不久的将来，基因疗法就能实现标准化/规模化的生产，让更多患者获益。”

Orchard secured a green light in the US for its metachromatic leukodystrophy (MLD) gene therapy on Monday, adding to several prior European approvals. The FDA clearance also bumps up the value of its acquisition by Japanese firm Kyowa Kirin that closed earlier this year. Lenmeldy (atidarsagene autotemcel) was approved to treat children with MLD, specifically those who are pre-symptomatic late infantile, pre-symptomatic early juvenile, and early symptomatic early juvenile. Those with the rare genetic disease are unable to produce the enzyme arylsulfatase A (ARSA), which results in a buildup of sulfatides in cells, damaging the central and peripheral nervous system and causing a loss of motor function, cognitive function, and early death. Lenmeldy is a one-time gene therapy that comprises autologous CD34+ cells genetically modified to encode the ARSA gene. Patients must undergo a chemotherapy conditioning regimen before receiving the infusion.Gene therapy boosts survivalThe approval was based on data from a pair of clinical trials and an expanded access programme that showed Lenmeldy significantly reduced the risk of severe motor impairment or death, compared with children who didn’t receive the gene therapy. In total, Lenmeldy was tested in 37 children. All pre-symptomatic late infantile patients reached their sixth birthday; based on natural history data, only about 58% of untreated children with MLD typically survive to six years old. Additionally, 71% of the gene therapy-treated children at age five were able to walk without assistance, and 85% of all evaluable patients had normal language and performance IQ scores.Cost-effectiveness pendingOrchard has not yet disclosed a list price for Lenmeldy, but the Institute for Clinical and Economic Review (ICER), a US drug pricing watchdog, said last year that the gene therapy would meet common thresholds for cost-effectiveness if priced between $2.3 million and $3.9 million. Atidarsagene autotemcel, also known as OTL-200, obtained EU approval as Libmeldy in 2020 as a one-time treatment for early-onset MLD. Libmeldy has also secured reimbursement in the UK, where it has a reported list price of more than £2.8 million ($3.4 million), as well as in Italy, Germany, Sweden, Iceland, Finland and Norway.Meanwhile, Monday’s approval triggers a bigger payout from Kyowa Kirin, which agreed in October to acquire Orchard for $16 per share, or about $387 million. An additional $1-per-share contingent value right was linked to US approval of the gene therapy, boosting the total buyout to about $478 million.

BARCELONA, Spain and DÜSSELDORF, Germany, Feb. 29, 2024 /PRNewswire/ -- Neuraxpharm Group (Neuraxpharm), a leading European specialty pharmaceutical company focused on the treatment of central nervous system (CNS) disorders, and Minoryx Therapeutics, a late stage biotech company focused on the development of therapies for orphan central nervous system disorders, reaffirm their commitment on Rare Disease Day 2024 to finding better treatments for patients suffering from a range of rare diseases, such as leukodystrophy, including X-linked adrenoleukodystrophy (X-ALD) and more specifically cerebral adrenoleukodystrophy (cALD). This Rare Disease Day, to raise awareness of this disease, Neuraxpharm and Minoryx announce the publication of a special information film with the participation of world renowned expert Professor Fanny Mochel, the Director of the Reference Center for Leukodystrophies - La Pitié-Salpêtrière Hospital, Paris, and Karen Harrison, Support Services Manager of Alex, The Leukodystrophy Charity (Alex-TLC). In the film, Professor Mochel describes the disease and the need for regular screening to identify patients as early as possible, while Karen Harrison speaks powerfully about the patient experience and need for better treatments. The film can be found on Neuraxpharm's and Minoryx's websites, YouTube and LinkedIn channels. Watch the film here. Dr. Jörg-Thomas Dierks, Chief Executive Officer of Neuraxpharm, said: "The impact this disease has on patients and their families cannot be overstated. At Neuraxpharm, we are committed to bringing better treatment to patients so that we can improve the lives of those affected by this devastating disease. We hope that this film will raise awareness and understanding of the condition." Marc Martinell, Chief Executive Officer of Minoryx said: "The X-ALD community deserve all our support to help them face the extremely challenging consequences of this disease, which in the case of cALD are fatal. We want to raise awareness of the diseases and the importance of regular monitoring and early detection as these are critical factors for timely management of these patients." On 26 January 2024, Neuraxpharm and its partner Minoryx Therapeutics stated that they are seeking a re-examination of leriglitazone, Minoryx's novel brain-penetrant and selective PPAR gamma agonist, by the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) for conditional approval for patients with cALD. Minoryx and Neuraxpharm strongly believe that leriglitazone has a positive benefit / risk balance in patients with cALD. About X-ALD and cALD X-linked adrenoleukodystrophy (X-ALD) is an orphan neurodegenerative disease. The global incidence of X-ALD is approximately 6-8/100,000 live births. Boys and adult men with X-ALD can, at any point in their lifetime, develop cALD, which is characterized by demyelinating brain lesions that may become rapidly progressive, leading to acute neurological decline and death. These lesions can produce severe symptoms such as loss of voluntary movements, inability to swallow, loss of communication, cortical blindness and total incontinence and death with a mean survival of 3 to 4 years. Progressive cALD occurs in 31-35% of ALD patients in childhood with typical onset between the age of 2-12 and up to 60% of adult patients, with X-ALD will develop progressive cALD over time. There is currently no pharmacological treatment available for cALD. In childhood, Hematopoietic Stem Cell Transplantation (HSCT) can arrest the disease. However, it is an aggressive procedure and only available for a portion of patients; autologous HSCT is not globally available; this still requires hemo-ablation therapy with associated comorbidities and long-term safety data is being gathered. In adults, experience in HSCT is very limited and the intervention is often not recommended. In addition, all X-ALD patients reaching adulthood develop adrenomyeloneuropathy (AMN), characterized by progressive spastic paraparesis, as well as progressive deterioration of balance and sensory function, and development of incontinence. This form progresses chronically with onset of symptoms typically in adulthood, affecting both men and women, and has poor prognosis. About leriglitazone Leriglitazone is Minoryx Therapeutics's novel orally bioavailable and selective PPAR gamma agonist with a potential first-in-class and best-in-class profile for CNS diseases. It has demonstrated brain penetration and a favorable safety profile. It showed robust preclinical proof-of-concept in animal models of multiple diseases by modulating pathways leading to mitochondrial dysfunction, oxidative stress, neuroinflammation, demyelination and axonal degeneration. In clinical trials, leriglitazone showed clinical benefit in both adult X-ALD patients in ADVANCE and pediatric X-ALD patients in NEXUS. Data from ADVANCE showed that leriglitazone reduces the progression of lesions and the development of progressive cALD. Results on radiological stabilization seen in NEXUS after 24 weeks of treatment were similar to those attained with Hematopoietic Stem Cell Transplant (HSCT) or ex-vivo gene therapy, hence it is expected that leriglitazone could provide a comparable clinical benefit to cALD patients. Leriglitazone has been granted orphan drug status for X-ALD from the FDA and the EMA and Fast Track and Rare Pediatric Disease designation from the FDA for the treatment of X-ALD. About the Neuraxpharm Group Neuraxpharm is a leading European specialty pharmaceutical company focused on the treatment of the central nervous system (CNS), including both psychiatric and neurological disorders. It has a unique understanding of the CNS market built over 35 years. Neuraxpharm is constantly innovating, with new products and solutions to address unmet patient needs and is expanding its portfolio through its pipeline, partnerships and acquisitions. The company has c.1,000 employees and develops and commercializes CNS products through a direct presence in more than 20 countries in Europe, two in Latin America, and globally via partners in more than 40 countries. Neuraxpharm is backed by funds advised by Permira. Neuraxpharm manufactures many of its pharmaceutical products at Neuraxpharm Pharmaceuticals (formerly Laboratorios Lesvi) in Spain. For more information, please visit About Minoryx Minoryx Therapeutics is a registration stage biotech company focusing on the development of novel therapies for orphan central nervous system (CNS) diseases with high unmet medical needs. The company's lead program, leriglitazone (MIN-102), a novel, brain penetrant and selective PPAR gamma agonist, is being developed to treat X-linked adrenoleukodystrophy (X-ALD) and other orphan CNS diseases. The company is backed by a syndicate of experienced investors, which includes Columbus Venture Partners, CDTI Innvierte, Caixa Capital Risc, Fund+, Ysios Capital, Roche Venture Fund, Kurma Partners, Chiesi Ventures, S.R.I.W, Idinvest Partners / Eurazeo, SFPI-FPIM, HealthEquity, Sambrinvest and Herrecha, and has support from a network of other organizations. Minoryx was founded in 2011, is headquartered in Spain with Belgian facilities and has so far raised more than €120 million. For more information, please visit