Sarepta Therapeutics, Inc.

PepGen is “temporarily pausing” a Phase 2 study of its exon 51 skipping drug for Duchenne muscular dystrophy, it said Tuesday. PepGen told Endpoints News via email that no patients have been enrolled in the paused study, which is recruiting at two sites in the UK, according to a federal clinical trials database . The neuromuscular disease biotech said it is planning to first review safety data for a cohort of patients enrolled in a separate, open-label study known as CONNECT1 that’s being conducted in Canada. It expects to have results from that group of four patients receiving a 10 mg/kg dose of PepGen’s drug, PGN-EDO51, in the third quarter. PepGen is currently facing queries from US and Canadian drug authorities on its Duchenne program, which is now further delayed. “This will allow us to gather additional safety data, assess the impact of this dose of PGN-EDO51 on dystrophin levels, and potentially improve the design of CONNECT2,” PepGen president and CEO James McArthur said in a statement. PepGen’s shares $PEPG fell 25% on Tuesday morning after announcing the pause. Exon skipping drugs are developed for patients with specific mutations and are meant to help “skip” over the faulty section of the RNA transcript for the muscle protein dystrophin to make a shorter but functional version of it. PepGen previously reported that two participants who received the 10 mg/kg dose of its drug in the CONNECT1 trial experienced abnormally low levels of magnesium. Then, in January, it said that those two patients returned to baseline magnesium levels after receiving supplements. One of the patients also experienced a decrease in a measure of kidney function called estimated glomerular filtration rate, and a subsequent scan indicated their eGFR was in the normal range. Canadian health authorities said then that the biotech can continue dosing at 5 and 10 mg/kg but have asked for additional safety information before any new patients at current or higher doses are enrolled in the CONNECT1 study. In December, the FDA put a clinical hold on PepGen’s request to start the CONNECT2 study in the US. The FDA had questions about the data behind the planned dosing levels for the study, according to PepGen. The company hopes to use the CONNECT2 study to ask for accelerated approval from the FDA, though those plans are now being delayed. PepGen said Tuesday that no new safety issues have been seen with its exon 51 skipping program. McArthur said in his statement that the study pause will let PepGen “focus resources” on its open-label study and its myotonic dystrophy type 1 program. As of the end of 2024, the biotech had $120.2 million in cash, which it said could fund its operations into 2026. In 2016, Sarepta Therapeutics won the first and widely controversial accelerated approval for an exon 51 skipping drug, Exondys 51. Biotechs like PepGen and Dyne Therapeutics are developing new exon 51 skipping drugs that they hope can be better than Sarepta’s therapy.

关注并星标CPHI制药在线 近日，基因疗法赛道不太平。前有基因治疗独角兽Bluebird Bio,Inc.（蓝鸟生物公司）被迫“卖身”，后有MNC巨头辉瑞退出基因疗法领域。接连发生的“变故”，不禁让人担忧基因疗法的商业化前景。该细分赛道还有翻盘机会吗？别急，成立44年的细胞基因疗法企业Sarepta Therapeutics已初次实现盈利。 从百亿市值到无奈卖身，蓝鸟无力回天 蓝鸟生物成立于1992年，其前身为Genetix Pharmaceuticals。2010年，公司更名为Bluebird Bio，并正式进入基因治疗领域。同一年，蓝鸟生物在《nature》发布文章，其基因疗法Lentiglobin在一项临床试验中，一位患有重型β地中海贫血的患者成功摆脱输血治疗。 β地中海贫血是一种罕见的遗传性血液疾病，由β-珠蛋白基因突变引起，其导致无效的红细胞生成从而造成严重贫血。患有该疾病的患者需要频繁输血来挽救生命，但也可能导致并发症，包括由于铁超载导致的器官衰竭。 Lentiglobin作为一种基因疗法，通过慢病毒载体将表达正常血红蛋白β亚基的基因在体外植入到从患者体内取出的造血干细胞中，再将这些细胞输入回患者体内，达到从根本上治疗β地中海贫血的目的，是一种潜在的革命性疗法。 该临床试验的公布，激起业内众多资本关注。2013年，蓝鸟生物顺利登陆纳斯达克。2018年，公司市值最高曾逼近300亿美金。不过，蓝鸟的高光时刻到此结束。 2019年，其首款基因疗法Zynteglo在欧盟获批上市，这是一种基于慢病毒载体的基因疗法，用于治疗β地中海贫血症，成为全球首个遗传性血液病的基因治疗产品。2022年，Zynteglo获FDA批准。该药物定价高达280万美元，高昂的价格曾被资本对其商业化前景寄予厚望。 打脸的是，Zynteglo的商业化现实远远不如预期。2021年，Zynteglo在欧盟的销售额仅为370万美元。由于患者数量有限，且无法与多个官方机构达成报销协议，蓝鸟生物最终在2022年初将该药撤出欧洲市场。 2022年，蓝鸟生物的第二款基因疗法Skysona获得FDA批准，用于治疗脑肾上腺脑白质营养不良（CALD），定价300万美元，成为当时全球最贵的药物。 2023年底，蓝鸟生物推出了第三款基因疗法Lyfgenia，用于治疗镰状细胞病（SCD），定价310万美元，再次刷新了全球最贵药物定价。 这两款药物的上市，仍未能给蓝鸟生物带来转机。安全性问题成为悬在蓝鸟生物头顶的达摩克利斯之剑。血液系统肿瘤是Skysona的主要安全问题。在接受Skysona治疗的67名受试者中，已出现3例恶性肿瘤病例，其中有2例在治疗2年后出现。经分析，FDA认为出现血液系统肿瘤风险是由于Skysona所使用的慢病毒载体Lenti-D在原癌基因中的整合导致的结果。并认为，随着时间的推移，很可能还会有更多的类似病例出现。 Lyfgenia更是遭遇了一系列挫折。2021年，由于患者有发展为急性髓性白血病的可能，FDA叫停了Lyfgenia用于18 岁以下镰状细胞病患者的临床试验。同时，由于和Lyfgenia使用了相同的慢病毒载体，Zynteglo也被暂停销售。最终，经过谨慎评估后，监管局认为治疗获益大于风险，遂继续允许Zynteglo的上市销售，并解除Lyfgenia临床试验暂停限制。经历重重挫折后，Lyfgenia于2023年底终于获批上市，然而已错过最佳时机，彼时Vertex Pharmaceuticals的CRISPR/Cas9基因编辑疗法Casgevy于同一年获批上市，同样用于SCD的治疗，且定价为 220 万美元，比Lyfgenia低。 安全性问题，再加上高昂的定价以及小众的患者群体，导致以上获批的三款产品至今未能打开市场。截至2024年11月，蓝鸟生物表示，仅启动了57例患者的治疗，其中Zynteglo有35例，Lyfgenia有17例，Skysona仅有5例。而在蓝鸟生物达成合作的70多家治疗中心中，只有40%为至少一名患者启动了治疗。 从2020-2023年，蓝鸟生物累计净亏损超40亿美元，在手握三款已上市基因疗法的局面下，公司2023年营收仅927万美元。目前，蓝鸟生物账上现金余额为 7065万美元，短期借款为7060万美元，算上其它负债，蓝鸟已经资不抵债。 此时被凯雷集团（Carlyle）和SK Capital Partners这类大型资本收购算是好的结局。根据交易条款，如果蓝鸟在2027年12月31日之前的任何12个月内，当前产品组合的净销售额达到6亿美元，Bluebird股东将获得每股3.00美元的现金和相当于每股6.84美元的或有价值权（CVR）。算上后续7000万美元的CVR，总和约1亿美元。 在基因疗法领域折戟的不仅仅是蓝鸟，“宇宙药厂”辉瑞也难逃商业化困境。 辉瑞：基因疗法大撤退 在蓝鸟生物宣布“卖身”的同一天，辉瑞也宣布将终止B型血友病基因疗法Beqvez（fidanacogene elaparvovec）的开发和商业化。该药系2014年，辉瑞从Spark Therapeutics（已被罗氏收购）获得。2024年，Beqvez获FDA批准，用于B型血友病的治疗，定价为350万美元。 遗憾的是，从批准上市至今，尚未有患者接受过该款药物的治疗。辉瑞对此表示：“患者及其医生对血友病基因疗法表现出的兴趣有限”。 辉瑞基因疗法的故事开始于2014年，当年12月8日辉瑞宣布将启动一个基因疗法平台，用于研究血友病和镰状细胞病等遗传疾病的潜在治疗方法，同时与Spark Therapeutics达成协议，共同开发针对B型血友病的基因疗法SPK-9001（Beqvez）。 在随后几年，辉瑞连续扩增基因疗法领域的布局。2016年，辉瑞以6.45亿美元的总金额收购Bamboo Therapeutics，率先布局杜氏肌营养不良症（DMD）基因疗法；2017年-2018年，辉瑞先后两次与Sangamo Therapeutics达成合作，布局肌萎缩侧索硬化症（ALS）和A型血友病基因疗法；2019年，辉瑞以6.3亿美元收购Vivet Therapeutics的15%股权，获得威尔逊病（Wilson Disease）基因疗法VTX-801的全球独家开发和商业化权利。 至此，辉瑞构建起了覆盖多种适应症的基因疗法产品。不过从2023年开始，辉瑞似乎在有意出清基因治疗管线。当年7月，辉瑞以高达10亿美元的价格将其临床前基因疗法项目出售给阿斯利康的罕见病部门Alexion。2024年9月，辉瑞基于现有临床数据，撤回了市场中所有批次的镰状细胞病（SCD）治疗药物 Oxbryta（voxelotor），还将停止所有正在进行的voxelotor的临床试验和全球扩展访问计划。 2024年12月，辉瑞终止了与 Sangamo Therapeutics 合作的血友病A基因疗法giroctocogene fitelparvovec。 近日宣布撤市的B型血友病基因治疗药物Beqvez，辉瑞曾付出了十年时间才获批上市，然而上市不到一年，由于商业化困境，辉瑞决定停止该产品的开发和商业化活动。 至此，辉瑞已经没有任何处于临床阶段和商业化阶段的基因治疗项目了。在长达十年的努力探索后，在研发和商业化等多种因素裹挟下，辉瑞最终还是折戟基因治疗赛道。那么，基因治疗真的没有明天吗？ 老牌药企开始盈利 关于基因治疗的未来，在此深耕44年的Sarepta Therapeutics或许更有发言权。Sarepta Therapeutics创立于1980年，于1997年上市，是一家专注于治疗罕见病、传染病和其他疾病的生物技术公司，也是基因疗法龙头企业。 2024年，Sarepta首度扭亏为盈，其2024年前三季度净利润为7619.00万美元，同比增长113.10%。业绩增长主要来源于旗下重组基因疗法——Elevidys，其将表达微抗肌萎缩蛋白的转基因包装在AAV病毒载体中，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，可以对携带任何类型DMD致病基因变异的患者生效。 Elevidys于2024年获FDA完全批准扩展适应症，将年龄至少为4岁的DMD患者纳入其中，这些患者携带DMD基因突变。2024年，Elevidys全年净收入达到8.208亿美元；是Sarepta业绩增长的主要驱动力。 另外公司在售基因治疗产品还有Exondys 51、Vyondys 53、Amondys 45，获批适应症为DMD等疾病。 基因疗法曾因“一次性治愈”的魅力深受资本青睐，后因安全性、商业化挑战、复杂的监管环境等障碍被一些入局者抛弃，但这并不能否认基因治疗的市场潜力。以Elevidys为例，目前估计在符合条件的潜在DMD患者群体中，其渗透率不足5%，这意味着该领域潜在市场份额将超过200亿美元。那么，如何在这一前沿技术领域打通终极的商业化闭环，这需要政策制定者、医疗系统、资本、药企等多方共同协作努力，探索新的支付模式和监管框架。未来基因疗法的商业化结局将会如何，我们持续关注。 参考来源： 1.蓝鸟公告 2.https://www.biospace.com/deals/bluebird-facing-cash-crunch-to-go-private-in-deal-valued-at-30m. 3.Pfizer Voluntarily withdraws all lots of sickle cell disease treatment Oxbryta (voxelotor) from worldwide markets. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-reports-preliminary-fourth-quarter-and-0. 4.Sarepta Therapeutics Announces Expanded US FDA Approval of ELEVIDYS to Duchenne Muscular Dystrophy Patients Ages 4 and Above. Retrieved June 20, 2024 from https://www.businesswire.com/news/home/20240620640445/en. 智药研习社近期直播预告 扫码领取CPHI & PMEC China 2025展会门票 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

Around 3.5 million people in the UK live with a rare disease, according to government data. Image credit: Shutterstock / H_Ko. UK patients living with rare diseases are not being offered many of the life-changing medicines being developed, mainly due to poor reimbursement criteria and weaker commercial opportunities. A survey, published by the Association of the British Pharmaceutical Industry (ABPI) and the Bioindustry Association (BIA) on Rare Disease Day (28 February), found that most pharmaceutical companies developing medicines for rare diseases do not expect their treatments to reach UK patients. Companies were asked last year to consider their pipeline rare disease assets with global launches within five years and assess how many would make it to the UK – a region where 3.5 million people live with a rare disease.  From the 18 respondents in the survey, 11 companies said that less than 75% of their pipeline is expected to launch in the UK over the next five years. The number of rare disease drugs in a company’s pipeline varies and may not always be publicly reported. Sarepta Therapeutics, a company specialising in rare diseases, has disclosed it has four candidates in the clinic with more at the discovery and preclinical stage. However, it is harder to ascertain the number of candidates in a big pharma company as not all programmes are publicly disclosed. According to ABPI, pharmaceutical companies’ low confidence in a UK launch stems from financial considerations. First, there is a low likelihood of a positive reimbursement decision from the National Institute for Health and Care Excellence (NICE). Treatments for rare diseases are generally more expensive than non-rare disease counterparts due to the small target patient population. Research has shown that orphan products for rare diseases are disadvantaged by NICE’s current appraisal model for new technologies. There is also the UK’s “increasingly unfavourable commercial environment”, as per ABPI, that puts off pharmaceutical companies. Rebate rates for medicines, the percentage of sales that drug developers are required to pay back to the NHS if sales exceed a pre-set target, are currently at 22.9%. The average between 2014 and 2022 was around 6.8%, with ABPI saying that rates are now “rocketing and unpredictable”. ABPI survey results indicate the knock-on effect – 16 out of 64 rare disease medicines approved for license in the UK were not submitted to NICE for evaluation. The result is that whilst there are more than 7,000 recognised rare conditions, only one out of 20 diseases has an approved NHS treatment or medicine. Call to arms The ABPI called for a greater ambition to make it easier to develop and launch medicines in the UK by making the region “a more attractive place”. The UK Government’s Rare Disease Action Plan 2024 highlighted the ongoing progress to advance the region’s rare disease capabilities, including a £14m investment into research platforms over the next five years. The document also details a framework comprising national priorities to raise awareness and care, increase diagnosis, and improve access to treatment and drugs. Initiatives by the government, however, have been far and few between, with researchers calling for better inclusion of rare disease strategies in public health strategies. Although welcoming the latest action plan, ABPI chief executive Dr Richard Torbett said: “Unless we address the UK’s historic and ongoing disinvestment in medicines, we will continue to see NHS patients with rare conditions missing out on the latest innovations. “This means fixing the current skyrocketing repayment rates under the Voluntary Scheme for branded medicines and making sure that the way NICE evaluates medicines for rare diseases does not prevent companies from bringing them to the UK.”