Vamorolone

Department of Health (DoH) of Hong Kong approved AGAMREE® for the treatment of Duchenne muscular dystrophy (DMD) in patients aged 4 years and older Follows recent approval from China’s National Medical Products Administration (NMPA) December 20, 2024 – Santhera Pharmaceuticals (SIX: SANN) announces that the Department of Health of Hong Kong, China, has approved AGAMREE® (vamorolone) for use in patients aged 4 years and older. The approval by the DoH of Hong Kong constitutes the fifth independent approval by local health authorities after the US FDA, EMEA, MHRA and the NMPA and will allow patients with DMD in Hong Kong access to AGAMREE in the near future. According to the license agreement between the companies first announced in January 2022, Sperogenix holds exclusive rights for the development and commercialization of AGAMREE for DMD and other rare disease indications in Greater China. This agreement was amended in March 2023 to include the option for several additional Southeast Asian countries, namely Brunei, Cambodia, Timor-Leste (East Timor), Indonesia, Laos, Malaysia, Myanmar (Burma), the Philippines, Singapore, Thailand, and Vietnam in exchange for a USD 4 million payment by Sperogenix. Sperogenix exercised this option in July 2024 to include these territories in their license agreement. Santhera is supplying AGAMREE to Sperogenix for both the ongoing Early Access Program (EAP) and for commercialization. Sperogenix will pay Santhera royalties at a double-digit percentage on net product sales, along with additional revenue-dependent milestones based on commercial sales. AGAMREE is a novel drug with a mode of action based on binding to the same receptor as glucocorticoids but modifying its downstream activity. Moreover, it is not a substrate for the 11-β-hydroxysteroid dehydrogenase (11β-HSD) enzymes that may be responsible for local drug amplification and corticosteroid-associated toxicity in local tissues [1-4]. This mechanism has shown the potential to ‘dissociate’ efficacy from steroid safety concerns and therefore AGAMREE is positioned as a dissociative anti-inflammatory drug and an alternative to existing corticosteroids, the current standard of care in children and adolescent patients with DMD [1-4]. In the pivotal VISION-DMD study, AGAMREE met the primary endpoint Time to Stand (TTSTAND) velocity versus placebo (p=0.002) at 24 weeks of treatment and showed a good safety and tolerability profile [1, 4]. The most commonly reported side effects were cushingoid features, vomiting, weight increase and irritability. Side effects were generally of mild to moderate severity. Currently available data show that AGAMREE, unlike corticosteroids, has no restriction of growth [5] and no negative effects on bone metabolism as demonstrated by normal bone formation and bone resorption serum markers [6]. References: [1] Dang UJ et al. (2024) Neurology 2024;102:e208112. doi.org/10.1212/WNL.0000000000208112. Link. [2] Guglieri M et al (2022). JAMA Neurol. 2022;79(10):1005-1014. doi:10.1001/jamaneurol.2022.2480. Link. [3] Liu X et al (2020). Proc Natl Acad Sci USA 117:24285-24293 [4] Heier CR et al (2019). Life Science Alliance DOI: 10.26508 [5] Ward et al., WMS 2022, FP.27 - Poster 71. Link. [6] Hasham et al., MDA 2022 Poster presentation. Link. Duchenne muscular dystrophy (DMD) is a rare inherited X-chromosome-linked disease, which almost exclusively affects males. DMD is characterized by inflammation which is present at birth or shortly thereafter. Inflammation leads to fibrosis of muscle and is clinically manifested by progressive muscle degeneration and weakness. Major milestones in the disease are the loss of ambulation, the loss of self-feeding, the start of assisted ventilation, and the development of cardiomyopathy. DMD reduces life expectancy to before the fourth decade due to respiratory and/or cardiac failure. Corticosteroids are the current standard of care for the treatment of DMD. Santhera Pharmaceuticals (SIX: SANN) is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular diseases with high unmet medical need. The Company has an exclusive license from ReveraGen for all indications worldwide to AGAMREE® (vamorolone), a dissociative steroid with novel mode of action, which was investigated in a pivotal study in patients with Duchenne muscular dystrophy (DMD) as an alternative to standard corticosteroids. AGAMREE for the treatment of DMD is approved in the U.S. by the Food and Drug Administration (FDA), in the EU by the European Medicines Agency (EMA), in the UK by the Medicines and Healthcare products Regulatory Agency (MHRA), in China by the National Medical Products Administration (NMPA) and Hong Kong by the DoH. Santhera has out-licensed rights to AGAMREE for North America to Catalyst Pharmaceuticals and for China and certain countries in Southeast Asia to Sperogenix Therapeutics. For further information, please visit www.santhera.com. Founded in 2019, Sperogenix Therapeutics is a platform company dedicated to developing and commercializing genetic disease and rare disease therapeutics in China. With prioritized therapeutic areas such as neuromuscular diseases and inherited metabolic diseases, Sperogenix is dedicated to establishing an innovative commercial model tailored to the China rare disease field, in order to provide affordable and reliable products and services to Chinese physicians and patients. In 2022, Sperogenix Therapeutics obtained the exclusive development and commercialization rights from Santhera Pharmaceuticals for AGAMREE® in DMD and all other rare diseases in the Greater China region (including Hong Kong, Macao and Taiwan) and the Southeast Asian region and production rights in all of the above regions under certain conditions. www.sperogenix.com. The content above comes from the network. if any infringement, please contact us to modify.

▎医药观澜/报道 本月，用于治疗杜氏肌营养不良症（duchenne muscular dystrophy，DMD）的伐莫洛龙口服混悬液（vamorolone）在中国获批上市，用于治疗4岁及以上DMD患者。这款药物是曙方医药1.24亿美元自Santhera Pharmaceuticals引进，此前该产品已在美国、欧盟等地获批治疗DMD。根据公开资料，这是在中国境内获批的首个DMD疗法，也引发了业界对这种致命罕见疾病的强烈关注。 DMD是一种罕见的肌肉萎缩疾病。患者由于编码抗肌萎缩蛋白（dystrophin）的基因发生变异，导致肌肉逐渐无力萎缩。有数据显示，全球约每3500-5000名男性新生儿中就有1名DMD患儿，每年约有2万名儿童确诊。患者预期寿命很少超过40岁。 令人欣慰的是，随着基因治疗技术的发展，越来越多针对DMD的治疗手段逐步出现。自2016年以来，已经有8款DMD疗法获得美国FDA的批准，同时旨在进一步提升疗效和安全性的更多在研疗法也在持续涌现。在即将结束的2024年，无论是全球还是中国，DMD药物研发领域也迎来了不少新进展。 中国十多款DMD管线在开发，多数处于早期阶段 根据公开资料，目前在中国针对DMD有十余款管线正在研发。这些在研管线主要包括寡核苷酸疗法、基因疗法和基因编辑疗法等，大多还在早期开发阶段，处于临床前或由研究者发起的临床研究（IIT）中。例如： 中美瑞康的RAG-18，一款小激活RNA（saRNA）药物。通过RNA激活机制特异性靶向激活肌肉细胞中UTRN基因表达。由UTRN基因编码的肌营养不良蛋白（utrophin）在结构和功能上与抗肌萎缩蛋白（dystrophin）相似，它的上调可功能性替代DMD肌肉细胞中缺失的抗肌萎缩蛋白，从而治疗所有突变类型的DMD和贝氏肌营养不良患者。RAG-18已获得FDA授予孤儿药资格与儿科罕见病药物资格。 迦进生物的CGB1002，一款抗体-siRNA偶联药物（抗体偶联PMO分子），拟治疗1型强直性肌营养不良症。它在临床前DMD动物模型上取得积极结果，单次给药后将全长肌营养不良蛋白恢复到健康组织水平的80%。 信念医药的BBM-D101注射液，一种重组腺相关病毒（rAAV）基因治疗药物，以工程化改造AAV作为载体，将优化的基因表达盒递送至全身肌肉以治疗DMD。它于今年下半年启动IIT研究。不久前FDA授予其治疗DMD的孤儿药资格和儿科罕见病药物资格。 新芽基因的GEN6050X注射液，一种使用双AAV9载体的静脉注射胞嘧啶碱基编辑药物，为适合外显子50跳跃的DMD患者设计，通过编辑突变的DMD基因，永久恢复肌营养不良蛋白的表达。该药物的IIT研究正在开展。 金唯科生物的JWK007注射液，一款AAV基因治疗药物，针对Dystrophin基因的各功能结构域设计了“迷你”抗肌萎缩蛋白基因，并在此基础上筛选出肌肉特异高效表达的基因表达框。今年9月其IIT研究首例受试者完成26周跟踪观察，安全性和有效性良好。 辉大基因的HG302，一种新型CRISPR DNA编辑疗法，通过基因编辑，恢复功能性肌营养不良蛋白的表达，进而改善肌肉功能，拟治疗DMD。今年12月，辉大基因宣布HG302已启动“肌肉MUSCLE”临床试验并完成了首例受试者给药。 此外公开信息显示，安天圣施、博雅辑因、北海康成等公司也均有临床前DMD管线。例如，安天圣施正在研发反义寡核苷酸（ASO）药物，推进针对DMD等适应症的研发管线。 寡核苷酸疗法，DMD治疗的重要研发方向 在全球领域，FDA已批准的8款DMD药物中，包括1款小分子、2款类固醇药物，还有1款腺相关病毒基因疗法以及4款寡核苷酸疗法。在这些疗法中，小分子组蛋白去乙酰化酶抑制剂和类固醇药物依然只能起到延缓疾病进展的作用，而基因疗法和寡核苷酸疗法可以针对DMD疾病的根本原因，即提高抗肌萎缩蛋白的表达，成为DMD疗法研发的重要方向。目前，除了已经获批的疗法，全球范围内还有几十款DMD疗法正处于临床开发阶段，其中过半为基因疗法和寡核苷酸疗法。 从作用机制来看，基因疗法可以将表达微抗肌萎缩蛋白（micro-dystrophin）的转基因包装在腺相关病毒（AAV）载体中，通过单次静脉注射，使得患者肌肉生成具有部分抗肌萎缩蛋白功能的重组蛋白。相比于基因疗法，寡核苷酸疗法生成的抗肌萎缩蛋白保存了野生型蛋白中更多的结构域，能够更好地模拟野生型蛋白的功能。并且，通过改变寡核苷酸疗法的序列，可以迅速使用这一治疗模式靶向其它基因或者突变。因此，这一药物类型备受关注。 目前，4款获FDA批准的DMD寡核苷酸疗法均采用吗啉代反义寡核苷酸（PMO）技术。PMOs是一类基于RNA天然框架设计的合成分子，它能够与特定mRNA前体序列结合，且在生物体内不易被降解，有着独特优势。不过这种疗法也有其局限性，例如组织渗透能力不强，不易被肌肉细胞吸收，或者在被细胞摄取后容易在溶酶体中被降解等。如何提高寡核苷酸疗法的组织特异性递送，在提高疗效的同时降低剂量，并扩展适用的疾病范围，成为这一领域的重要研发方向。 为提升PMO疗法的临床效果，新一代寡核苷酸药物也在合成工艺等方面持续创新。其中一种方式便是将寡核苷酸与细胞穿透肽（CPP）相偶联，形成称之为PPMO的新一代疗法。CPP由少于30个氨基酸组成，具有两亲性或阳离子性，能够携带大分子生物载荷穿透细胞膜，从而增加寡核苷酸的细胞和组织渗透性，这使药物在低剂量时便具有增强的疗效。 2024年，国际领域有多款临床阶段的PMO/PPMO疗法迎来新进展。例如，PepGen公司通过其专有平台开发的PPMO疗法PGN-EDO51也正在临床2期试验中，评估其在适合外显子51跳跃基因突变的DMD患者中的疗效与安全性。其专有CPP可增强细胞摄取，并促使寡核苷酸在被溶酶体降解前成功逃逸；同样地，为应对溶酶体降解的挑战，Entrada Therapeutics开发了ENTR-601-44，这款疗法由该公司专有的内体逃逸载体（EEV）多肽与PMO偶联，旨在治疗适合接受外显子44跳跃疗法的DMD患者。今年6月发布的1期临床试验结果显示，与安慰剂组相比，接受ENTR-601-44治疗的患者，其外显子跳跃水平显著提高，具统计学意义。 这些进展展示了新型寡核苷酸药物的未来潜力，更有望为DMD患者带来新的治疗选择。 CRDMO平台赋能寡核苷酸疗法研发，造福DMD等罕见病患者 尽管PMO、PPMO相关寡核苷酸疗法对于患者而言意义非凡，但这类疗法的开发难度大，需要极为复杂的工艺技术。 药明康德在化学业务上20多年的丰富经验，为开发这类新疗法打下了坚实的基础。作为全球赋能寡核苷酸药物研发的一体化、端到端的CRDMO平台，药明康德目前具备PMO单体、PMO、多肽、PPMO偶联及制剂开发的综合能力，可以提供“一站式”解决方案。公司寡核苷酸、多肽、制剂、分析等6个团队平行推进、无缝衔接，曾经将一款来自客户的PPMO在研疗法仅用11个月推进至IND。 公开信息显示，药明康德化学业务平台的新分子板块（WuXi TIDES）于2018年布局，在多肽和寡核苷酸等新分子的开发和生产方面持续精进平台能力，通过不断优化工艺、内部整合流程提供一体化服务，在3年内将PMO类药物活性成分（API）成本降低60%。这也得益于药明康德在CMC一体化解决方案方面的专精与专长。目前WuXi TIDES平台正在为三款治疗DMD的PMO和PPMO药物提供研发赋能。 DMD是全世界7000多种罕见病中的其中一种，考虑到寡核苷酸疗法的作用机制，此类疗法有望让更多罕见病患者从中受益。药明康德在开发包括吗啉代反义寡核苷酸（PMO）和多肽-PMO偶联物（PPMO）在内的寡核苷酸药物方面的全面能力，有望为DMD，乃至更多罕见病患者带来福音。 本文来自药明康德内容团队，欢迎个人转发至朋友圈。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。