Givinostat Hydrochloride

2024年3月21日美国FDA批准吉维诺司他(givinostat)用于治疗6岁及以上杜氏肌肉营养不良症(Duchenne muscular dystrophy，DMD)患者。吉维诺司他是首个被批准用于所有DMD患者的非甾体类药物，其推荐服用剂量需根据患者体质量确定，一日2次随餐服用。DMD是最常见的儿童型肌肉萎缩症，是一类罕见的神经系统疾病，表现为进行性肌肉无力，最终累及呼吸肌导致患者死亡。一项为期18个月的随机双盲对照Ⅲ期临床研究为吉维诺司他的获批上市提供临床证明。该研究主要终点事件为基线期到第18个月肌肉功能改善情况(以四级楼梯攀登评估)；次要终点基线期到第18个月北极星移动评价量表(North star ambulatory assessment，NSAA)评估的身体功能改善情况。结果显示，与安慰剂相比，接受吉维诺司他治疗者爬四级楼梯所需时间显著降低，NSAA评分恶化率更低。吉维诺司他常见不良反应腹泻、腹痛、血小板减少、恶心呕吐、三酰甘油水平升高及发热。因此，吉维诺司他处方信息中明确指出，在开具吉维诺司他处方前应检测患者血小板计数及三酰甘油水平，若血小板计数＜150×109/L则不应服用该药。治疗期间应监测血小板计数及三酰甘油水平，以及时调整剂量。此外，吉维诺司他可能导致QTc间期延长，增加心律失常风险，故部分类型心脏病患者应避免服用该药。参考：FDA官网本刊主管单位为上海医药工业研究院，由上海医药工业研究院、中国药学会主办，原名《国外医药——合成药、生化药、制剂分册》，1980年创刊，2003年起经国家新闻出版总署批准更名为《世界临床药物》。曾获国家“医药信息成果奖”、华东地区优秀期刊等奖项。为中国科技核心期刊（中国科技论文统计源期刊）、中国学术期刊综合评价数据库来源期刊、中国生物医学期刊文献数据库统计源期刊、中国学术期刊评价报告RCCSE中国核心（扩展版）学术期刊，被药学文摘、美国化学文摘（CA）和波兰哥白尼索引（IC）等收录。本刊全面介绍国内外最新药物治疗信息、临床用药经验和药物不良反应。目前设有 “医药专论”、“研究论文”（论著，简报，探讨&交流）、综述评论（药物开发，临床研究，应用评价，政策管理，医药市场）、信息（全球医药快讯，上市新药，治疗指南）等栏目，特邀临床专家解读最新治疗指南，由国内临床一线专家参与组织和撰写的专题综述，颇具权威性和指导意义。对国外临床指南及其更新的关注和点评，客观全面的药物疗效及不良反应评价，均有助于我国医疗卫生事业的发展，切实提高我国临床用药水平。本刊主要面向临床医师、药师和药事管理人员，以及医药企业、高等院校、研究机构的科研、管理和营销人员，是我国医药工作者了解全球医药动态的专业媒体。本刊得到国内临床知名专家和权威人士的大力支持，编委有来自全国临床一线的资深专家、科研院所及高等院校的医药研发工作者。刊物发行面广，读者覆盖全国30多个省市的三级甲等和二级甲等医院数千家。END如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

Pictured: 3D rendering of human cells and DNA/iStock/iStock, anusorn nakdee 2023 was a banner year for cell and gene therapy, with seven FDA approvals, according to the Alliance for Regenerative Medicine. And the pace doesn’t appear to be slowing at all as the second quarter of this year gets underway. The advocacy group is anticipating an even bigger year for the CGT space in 2024, with a potential 17 approvals in the U.S. and EU combined, according to ARM’s annual Cell & Gene State of the Industry Briefing in January. “It seems like the FDA is really pushing forward with accelerated approvals for cell and gene therapies, and that’s quite encouraging to see,” Jack Allen, a senior research analyst at Baird, told BioSpace. “These can be quite expensive products to develop, and if we’re able to leverage abbreviated pathways to get them to market rapidly, I think that can really reignite enthusiasm for the space.” Allen noted that cell and gene therapy is somewhat de-risked by the fact that, in many instances, these treatments involve introducing the genetic sequence for a native functional protein. “I think there will be some bumps in the road as it relates to pressing forward rapidly with the technology,” he said, but “it seems like the FDA has buy-in and is willing to ride through some of those bumps.” Here, we take a closer look at six of the more notable cell and gene therapies approved during the past year—two of them under the FDA’s accelerated approval pathway—and preview some of the decisions on the horizon. Cell Therapies BMS’s Breyanzi Chronic lymphocytic leukemia and small lymphocytic leukemia On March 14, the FDA approved Bristol Myers Squibb’s Breyanzi as the first CAR T cell therapy for relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia. In the pivotal TRANSCEND 004 trial, Breyanzi elicited a complete response—something that is “basically unheard of” in patients with relapsed/refractory CLL, according to Rosanna Ricafort, vice president and head of late development hematology and cell therapy at BMS—in 20% of recipients, with responses lasting more than 35 months. The Big Picture In November 2023, the FDA launched an investigation into the “serious risk” of secondary malignancies in patients treated with BCMA- or CD19-directed autologous CAR T cell therapies. This led to the addition of a boxed warning to all six commercial CAR-T therapies at the time, including BMS’s Breyanzi. But industry leaders and the FDA itself have been supportive of CAR-T’s risk/benefit profile. Breyanzi’s approval in two more indications, along with the recommendation of FDA advisers to move Abecma and J&J’s Carvykti into earlier lines of treatment for multiple myeloma, have cemented this tone. Iovance’s Amtagvi Melanoma In one of the year’s most anticipated decisions, the FDA in February greenlit the first one-time cell therapy for a solid tumor, Iovance Biotherapeutics’ Amtagvi for unresectable or metastatic melanoma, under the accelerated approval pathway. Iovance is currently conducting a confirmatory study to verify the therapy’s benefit. The Big Picture Amtagvi is the first tumor-infiltrating lymphocytes (TIL) therapy, a treatment modality some experts say has advantages over CAR-T. While CAR Ts recognize only a small number of proteins on the surface of tumor cells, TILs can identify tumor targets derived from intra- or extracellular tumor proteins, Sammy Farah, CEO of Turnstone Biologics, told BioSpace. As of February 2023, there were more than 75 TIL immunotherapies in preclinical or clinical studies for various indications. Gene Therapies Orchard Therapeutics’ Lenmeldy Metachromatic leukodystrophy Last month, the FDA approved Orchard Therapeutics’ Lenmeldy as the first gene therapy for metachromatic leukodystrophy (MLD), a rare, degenerative disease characterized by loss of motor and cognitive function and early death. MLD is caused by a deficiency in the arylsulfatase-A (ARSA) gene, leading to a buildup of fatty substances in the cells. Lenmeldy is a single-dose infusion made from a patient’s own hematopoietic stem cells, which have been genetically modified to include functional copies of the ARSA gene. The Big Picture Lenmeldy joins a growing list of gene therapy firsts in pediatric diseases, including Sarepta’s Elevidys for Duchenne muscular dystrophy and bluebird bio’s Skysona for cerebral adrenoleukodystrophy. It is also the first FDA-approved treatment for MLD patients, “who previously had no treatment options beyond supportive and end-of-life care,” Orchard CEO Bobby Gaspar said in a statement. Vertex and CRISPR Therapeutics’ Casgevy Sickle cell disease, beta thalassemia Possibly the most celebrated approval of 2023 went to Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy, which in December became the first-ever CRISPR-based gene editing therapy in the U.S., for sickle-cell disease (SCD). Just one month later, Casgevy was also approved for transfusion-dependent beta thalassemia, more than two months ahead of its PDUFA date. The Big Picture Casgevy’s SCD approval came just over a decade after the publication of the Nobel Prize-winning CRISPR-Cas9 technology—a timeline many industry experts have deemed faster than what would normally be expected of a new modality. But CRISPR is not without its risks. Researchers have cited cell toxicity and genomic instability as potential side effects, which could potentially trigger tumor development. Scientists are now working to improve on the technology with new modalities, including base editing and epigenetic editing. Bluebird bio’s Lyfgenia Sickle-cell disease While the historic nature of Casgevy’s approval won the day, bluebird bio’s Lyfgenia, a lentiviral gene therapy, also got the FDA’s nod for SCD on Dec. 8, 2023. Treatment with Lyfgenia led to the complete resolution of vaso-occlusive events 6 to 18 months after infusion, making it another promising option for patients. The Big Picture Allen said Lyfgenia may have a couple of advantages in the SCD market. “Both [therapies] are incredibly transformative in that they effectively eliminate sickle-cell disease–induced pain crises. Lyfgenia I think is quite interesting in that there’s a longer durability of data . . . and they also have some data in stroke patients, which I think is going to be differentiating in the commercial marketplaces” given the prevalence of stroke in SCD. Lyfgenia also has the upper hand over Casgevy in terms of developing the infrastructure needed to deliver treatment to patients. Sarepta’s Elevidys Duchenne muscular dystrophy In one of 2023’s more controversial decisions, the FDA approved Sarepta Therapeutics’ Elevidys as the first gene therapy for Duchenne muscular dystrophy (DMD). Elevidys missed the primary functional endpoint in a randomized trial but won accelerated approval based on data showing it increased the expression of the micro-dystrophin protein—a biomarker the agency determined is “reasonably likely to predict clinical benefit” in DMD patients 4 to 5 years of age. The FDA’s green light followed an adcomm meeting where its advisers narrowly recommended the gene therapy for approval. Then, just four months after the approval, Elevidys failed a confirmatory trial. The Big Picture Elevidys’ approval kicked off a wave of momentum in the DMD space. In October 2023, the FDA authorized Santhera Pharmaceuticals’ Agamree, and just last month, Italfarmaco won approval for Duvyzat, the first nonsteroidal drug approved to treat patients with all genetic variants of the disease. On the Horizon Rocket’s Kresladi Leukocyte adhesion deficiency-I Rocket Pharmaceuticals had expected a decision on its gene therapy Kresladi, in development for the rare disease leukocyte adhesion deficiency-I, in March, but the FDA pushed the date back to June 30, 2024 in order to allow for more review time. BMS’s Breyanzi Follicular lymphoma and mantle cell lymphoma It’s a big year for BMS’s Breyanzi, as the company is expecting the FDA to decide on the CAR T cell therapy as a treatment for patients with relapsed or refractory follicular lymphoma on May 23 and for those with relapsed or refractory mantle cell lymphoma who have been treated with a Bruton tyrosine kinase inhibitor therapy on May 31. Pfizer’s Beqvez Hemophilia B After winning approval in Canada in January, Pfizer’s adeno-associated virus-based gene therapy fidanacogene elaparvovec—marketed as Beqvez in Canada—has a PDUFA date in the second quarter of 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.