Voretigene Neparvovec

iStock, Deagreez In the wake of multiple patient deaths from liver injuries related to Sarepta Therapeutics’ AAV gene therapy platform, some in the sector are looking for ways to improve the current technology, while others are eager to move on. If a patient is a good candidate to receive a gene therapy, delivering it using an adeno-associated virus (AAV) is a natural choice. AAVs are the current standard bearer for delivering functional genes to patients with genetic diseases. Duchenne muscular dystrophy (DMD)—a lethal muscle disease caused by mutations in the dystrophin gene—is a natural candidate for gene therapy. But Sarepta Therapeutics’ recent, well-publicized saga has rocked the gene therapy space. Within the last few months, two patients with DMD who received the company’s AAV gene therapy Elevidys died from liver injury, as did a patient in a Phase I clinical trial for the company’s limb-girdle muscular dystrophy gene therapy SRP-9004, which uses the same underlying platform technology as Elevidys. The issue with AAVs in these cases is a problem for just about anything that enters the bloodstream: they accumulate in the liver. That’s not a problem unique to this technology, but its significance lies in one of the major drawbacks of using AAVs: their immunogenicity. “Everything goes to the liver, not just viruses,” Nitin Joshi, a bioengineer and assistant professor at Harvard Medical School whose lab develops gene therapies for a variety of disorders, told BioSpace . “This is an issue for all drugs, including small molecules.” It’s a bigger problem with AAVs, however, because viruses can raise a response from the immune system, causing damaging effects like cytokine storm, he explained. AAVs were discovered in 1965 and quickly recognized for their ability to deliver DNA into cells. In 1984 , scientists demonstrated a landmark proof of concept: AAVs could deliver a gene to a mammalian cell. Novartis’ Luxturna , which in 2017 became the first-ever FDA-approved gene therapy, for a rare form of inherited vision loss, is delivered using an AAV vector. Now, with a spate of high-pro on its docket, the gene therapy space is asking itself questions about AAV, its old reliable workhorse. Even before the recent deaths connected to Elevidys, thirteen deaths were linked to AAV gene therapy between 2021 and 2024, according to an article published by the Norn Group. After news of the third death linked to Sarepta’s platform broke, fears for AAV’s future exploded on social media. Zhonghao (John) Liu, founder and CSO at YOLO Immune, compared the situation to the death in the 1990s of Jesse Gelsinger after being injected with an experimental gene therapy using an adeno-virus vector to treat his genetic disease of urea cycle disorder. The FDA stopped all ongoing gene therapy trials at that time, Liu wrote in a LinkedIn post in late July. “Today’s event may become the second turning point for the whole gene therapy field! Chilling Winter Is Coming!” But AAV’s demise may have been greatly exaggerated. “AAVs will have value in the long run,” Emil Kakkis, CEO of Ultragenyx, told BioSpace. A Real Sponge for Drugs AAVs are popular—even among the suite of other viruses available to deliver drugs, like retroviruses—for a very specific reason: they can deliver DNA directly to the nucleus of non-dividing cells. That separates them from retroviruses, which can only target dividing cells, and lentiviruses, which can target non-dividing cells but struggle to deliver DNA to the nucleus, where it can be expressed stably. That opens up the virus’ tissue-targeting abilities far beyond other viral and nonviral platforms. Sarepta, Elevidys and the liver injuries sustained by patients taking the drug have not come under the spotlight because patients with DMD are especially susceptible to liver side effects. In contrast, myotubular myopathy, another genetic condition that produces severe muscle weakness, does cause liver problems on its own. In 2020 , two patients taking an experimental AAV-delivered therapy for myotubular myopathy made by Audentes Therapeutics (now a part of Astellas Pharma) died of liver injury. “But unlike myotubular myopathy, DMD patients don’t have underlying liver disease usually, and [it] also seems like liver failure in the three Sarepta cases are more consistent with AAV-associated immune reaction,” Joshi told BioSpace in a follow-up email. Instead, in DMD, the problem is that AAVs accumulate exceptionally well in the liver but are difficult to target anywhere else. Dystrophin is mutated in the muscle, which AAVs do not target particularly well. Also, since muscle is distributed throughout the body, a replacement gene needs to be delivered systemically as opposed to locally. Because muscle is such a tricky tissue to target, gene therapies for DMD need to use AAV doses several orders of magnitude higher than those for a genetic disease related to the liver, Kakkis explained. That is why DMD patients are experiencing liver injuries: they are simply receiving much, much more virus than patients with other conditions, he said. “For liver conditions, you don’t need a higher dose,” Kakkis said. “For other places you need to increase the dose.” This also comes down to issues with manufacturing AAVs. It is difficult to prepare fully potent AAVs where every single capsid contains a therapeutic gene. According to Kakkis, a therapeutic dose of a gene therapy’s DNA can be made up of up to 50% empty viruses, meaning patients are getting double the dose of virus that they actually need. However, Sarepta’s struggles do not mean the end of AAVs. A bevy of companies, including KBI Biopharma and BioChromatographix , in addition to academic scientists, are actively researching methods —like ultracentrifugation and particular kinds of chromatography—to separate out empty capsids in an AAV preparation, potentially lowering the effective dose for gene therapies like Elevidys. Another popular fix for AAV’s struggles with liver injuries is to give patients steroids along with their gene therapy in an attempt to muffle an immune reaction to the virus. According to Kakkis, this has long been a common approach for gene therapy companies, and one Ultragenyx is employing in its Sanfilippo syndrome program. Ultragenyx received a Complete Response Letter from the FDA last month for its Sanfillippo candidate UX111, also an AAV-based gene therapy. The regulator cited manufacturing concerns, but Kakkis remained confident in the company’s viral technology. “We have been testing AAVs in four different conditions with no safety issues. We look at AAVs as a very safe format and we’re invested in it,” he said. “With continued improvement in AAV technology, it’ll be around for a very long time.” Beyond AAV While some in the gene therapy industry look to fine-tune AAVs for greater safety, others are charting a course away from the old stalwart. One of these individuals is Harvard’s Joshi. “It’s the holy grail [of gene therapies] to move away from viral vectors,” he said. “The field agrees we need new materials with the ability to transfect cells.” Other gene delivery platforms, particularly lipid nanoparticles (LNPs), have come to the fore as alternative methods. LNPs have the simple advantage of not being a virus and therefore having much lower immunogenicity, avoiding the liver injury complications of AAV-based therapies. While not a gene therapy, Moderna’s mRNA-based COVID-19 vaccine Spikevax uses LNPs to deliver its payload. It sidesteps a key issue with LNPs that echo AAVs’ issues: they’re difficult to target anywhere but the liver. Moderna doesn’t have that problem because its vaccine can be delivered into the bloodstream without much targeting and still raise an immune response. It’s not just vaccines that are leveraging LNPs. Alnylam’s Onpattro , an siRNA therapy for hereditary amyloidosis, uses an LNP vehicle to deliver its payload. However, this is again a liver-directed condition, so targeting is not an issue. Kakkis reiterated that AAVs are here to stay, even if further improvements in dosing and immunogenicity are needed. “I look at Sarepta’s drug as a first-generation drug. What Sarepta’s done is open the door to other improvements,” he said, pointing to companies like Solid Bioscience that are developing next-generation delivery systems. “We have been testing AAVs in different conditions [like Sanfilippo syndrome and Wilson disease] with no safety issues,” he said. “I think AAVs are a very safe way to deliver DNA to the liver. With continued improvement in AAV technology, it’ll be around for a very long time.” And the stakes for patients, especially those with DMD, are extremely high. “There are kids living and dying today, so it’s now or never, not three to five years from now on. In that setting, the treatment has value.”

这一轮创新药板块性行情，演绎的无比极致，无论是属于基本面投资者能力范围内的龙头Biotech，还是属于概念趋势投资者的新芽药企，都走出了属于各自的一波行情。 成熟投资者，要理解基本面驱动的逻辑，也要理解资金面驱动的逻辑。 正是有这么一家创业板的药企，在一个月的时间内涨了100%，短期涨幅冠绝创业板的绝大多数生物医药企业，并且该企业对外交流并不多，以至于很多投资人甚至不知道公司在涨什么，它就是海特生物。 海特生物2024年年报显示，公司核心业务为药品制造和医药研发服务，前者主要核心产品为注射用鼠神经生长因子“金路捷”，2024年收入约1.2亿人民币；后者则分为两块，一个是仿制药为主创新药为辅的CRO-CDMO一体化服务，一个则是提供API和原料药CDMO解决方案，2024年实现约4.11亿人民币收入。即便是如此，公司在2024年依旧录得了归母净利润-6934.87万，2025Q1则录得了归母净利润-1393.04万。 显然，仅仅看海特生物目前固有的业务是找不到公司市值暴涨的任何逻辑，事实上市场把公司视为一个”高价值的创新药资产包“，包括现有在销售的创新药长期市场潜力和参股公司进度靠前的创新药管线价值，这给予了市场较大的想象空间，本文借此进行梳理分析。 01 MM新药的新拓展 海特生物在近年来有一个全新的增长点，便是创新药注射用埃普奈明（以下统称“沙艾特”）在2023年11月获批上市，并且在2024年5月正式商业化销售（当年录得销售额2636.83万元），2025年1月1日正式纳入国家医保目录。 沙艾特全球首个且唯一上市的死亡受体4/死亡受体5（DR4/DR5）激动剂，沙艾特作用机制与TRAIL（肿瘤坏死因子相关凋亡诱导配体）相同，与DR4/DR5结合激活凋亡通路，通过“外源性凋亡通路”杀伤肿瘤细胞，且具有p53非依赖性。 目前沙艾特联合沙利度胺和地塞米松获批既往接受过至少2种系统性治疗方案的复发或难治性多发性骨髓瘤（RRMM）成人患者，由此可知其目标群体为后线/末线MM患者，与CD38抗体、TCE、BCMA CAR-T等新型治疗手段同台竞技。 同被纳入医保目录且被CSCO指南推荐治疗RRMM的卡非佐米，被视为沙艾特的合适参照物之一，卡非佐米2023年全球销售额达14.03亿美元，而在国内2023年销售额约合2.86亿元人民币（2022年初上市供应）。 沙艾特在RRMM治疗优势主要有几点： 1）安全性良好-卡非佐米治疗出现的心脏、肺、肾、胃肠、神经毒性，沙艾特主要不良反应为肝毒性，多为轻度，大部分患者无需干预即可恢复，患者具有更好的耐受性； 2）疗效-在同类RRMM人群中，沙艾特方案在OS和DOR上均比卡非佐米方案延长≥6 个月，且对p53缺失等高危亚组优势更大（非头对头）； 基于卡非佐米的商业化情况和沙艾特自身独特优势，沙艾特今年有机会冲击2-3亿元甚至以上的销售额，并且有望在国内冲击10亿元的销售额。 值得注意的是，沙艾特的叙事并未在RRMM领域止步。 临床前及早期临床显示，沙艾特可与蛋白酶体抑制剂、免疫调节剂、BCMA CAR-T等 多种机制药物协同，进一步增强肿瘤细胞凋亡并重塑免疫微环境，这意味着该药物可能跟其他新型药物并非竞争甚至是互补的关系。 据管理层介绍，沙艾特可能通过影响免疫微环境的方式，对接受CAR-T细胞回输的患者体内的CAR-T细胞扩增产生积极影响，国内部分一线血液病医院也与公司合作开展沙艾特用于CAR-T前桥接化疗及CAR-T后的维持治疗等方向的临床研究。 另外，沙艾特正在进行实体瘤的拓展，进度最快的为肉瘤（骨肉瘤/软组织肉瘤）。 02 眼科药物的突破性 在眼科领域，海特生物有两项重要的布局，一是公司自主研发了HT006.2.2滴眼液，二是战略投资了眼科遗传病基因治疗领域的中眸医疗（占比15.38%）。 HT006.2.2滴眼液活性成分是重组人神经生长因子（rhNGF），核心适应症为中、重度神经营养性角膜炎（NK），目前处于Ib期临床，据介绍其经处方优化后稳定性优于同类产品Cenegermin。 对标产品Cenegermin是全球首个用于治疗中重度NK局部生物制剂，作为一线或二线非手术方案，适用于传统保守治疗失败或手术高风险NK患者。 不过，NK的发病率低于万分之五，患者总体人数不算大且诊出率较低，相对而言潜在市场空间有限，若未来rhNGF能拓展至其他角膜神经损伤相关适应症，会有更大市场空间。 海特生物更令人注意的布局是战略投资中眸医疗。 中眸医疗的核心管线是ZM-02，这是一种光遗传基因疗法，是全球首款广谱视网膜色素变性（RP）基因治疗药。 ZM-02的核心机理是通过以AAV为载体将“人造光敏蛋白表达基因”下游不感光的视网膜细胞膜，从而恢复患者视网膜对光的信号和视力，据公司介绍该类疗法适用于光感受器凋亡的患者，包括晚期RP、晚期黄斑萎缩AMD等。 已有临床前及临床数据显示，在动物模型中，中眸医疗筛选出的光敏蛋白（PsCatCh2.0）将失明小鼠的视力恢复到相当于人类视力的0.3左右；人体临床中，两位已入组视网膜色素变性患者都出现了视觉功能的明显提升。值得注意的是，该疗法为基于AAV的基因治疗，能够做到一次注射长期有效。 （患者治疗两周后的视力改善对比  图源：生辉） 仅以RP适应症为例，美国潜在患者人数可能高达10万人，而中国患者规模可能超过百万，中重度患者占到其中的60-70%。目前全球范围缺乏有效的治疗手段，唯一上市的基因疗法Luxturna仅限RPE65突变相关RP，2023年销售5800万 美元，2024年受限于免疫性难题和产能不足。而ZM-02是广谱性的基因治疗，不受视网膜色素变性的特定基因突变类型限制，拥有更宽阔的市场空间。加上老年性黄斑变性中的晚期黄斑萎缩（GA）约占晚期AMD的20–25%，推算全球GA患者150–200万人，中国预计30-40万人，市场空间更大。 尽管中眸医疗对目前自家ZM-02管线的阶段性估值为96.55亿人民币确实有些乐观，但ZM-02的广阔市场空间和眼科重磅炸弹的潜力不可否认，需要进一步在临床验证有效性和安全性数据。 03 参股公司小分子PCKS9，进度靠前 早在2021年，海特生物对西威埃医药进行增资，增资完成后持有该公司约13.64%的股权（第三大股东），这项布局也使得海特生物一只脚踏入了心血管创新药领域。 西威埃医药是一家专注于心血管和肝脏代谢疾病创新药的Biotech，其核心管线是口服小分子PCSK9抑制剂CVI-LM001，另外还有进入临床的THR- β选择性激动剂CVI-2742，在治疗NASH和NAFLD患者方面具有同类最佳潜力。 尽管CVI-LM001暂未公布最新的II期临床数据，其在Ib期药效探索研究就已经看到明确的初步疗效证据（相比安慰剂组治疗组导致血液LDL-C水平显著降低）。 从进度上看，目前口服PCSK9全球第一梯队的管线为默克的Enlicitide（小分子化药）和阿斯利康的AZD0780（口服多肽），均处于临床三期（默克占得先机），第二梯队则是诺和诺德的NNC0385-0434、西威埃的CVI-LM001，均处于临床二期。 目前市场上获批的PCSK9药物均为注射剂型，尽管首个siRNA药物出现展现了一定的竞争格局的变化，但整体PCSK9药物市场仍然在2024年保持总体规模的强劲增长。 海外行业专家评论表明，如果疗效和耐受性相当，口服PCSK9药物有潜力完全取代注射剂型；并且，海外分析师预测默克的Enlicitide峰值销售额有望达到40亿美元。 CVI-LM001有望成为国内最快进入临床三期的口服PCSK9分子之一，未来有望实现授权出海，与合作伙伴分享全球百亿美元市场。 结语：在2024年的年报里，海特生物体内看起来“真的没什么东西”，但这不妨碍公司”全新商业化创新药+体外一众FIC的管线资产包“被市场投资者视为“香饽饽”，不说未来兑现如何，至少它们叙事的宏大性和故事性，是令人多巴胺拉满的。 识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！ 请注明：姓名+研究方向！ 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。