Ratio Therapeutics, Inc.

一场由“核”引发的创新药新赛道风口已经到来。 据Evaluate的预测，2026年放射性药物疗法的年销售额将超过60亿美元。如果算上诊断试剂，市场规模还要翻一番。核药正迅速成为MNC和投资者的新宠。 过去几年，核药领域共进行了约86笔战略交易，特别是2022年，交易数量相比2021年翻了近3倍。从融资事件来看，核药领域发生的融资数量稳步上升。融资规模也在提高。如2023年前三季度的平均融资额（5100万美元）已经是2018年2600万美元的2倍。 今年部分MNC在核药领域的重磅交易，根据公开信息收集整理 到了2024年，核药赛道非但没有熄火，反而越烧越旺，已然成为全球制药巨头们的必争之地。 就在9月份，赛诺菲以3.2亿欧元的投资，宣布加入“核药”市场竞争，与RadioMedix和Orano Med达成独家许可协议，共同开发基于同位素铅（lead）的放射性配体疗法（RLT）用于癌症治疗。 赛诺菲此次进军核药领域，是其在医药版图上的又一战略性扩张。特别是在拳头产品度普利尤单抗专利即将在未来几年到期的情况下，赛诺菲迫切需要找到能够接棒的产品。 尽管过去2年，已有多个重磅交易，但到了2024年多家MNC非但没有放缓节奏，反而大额交易频出，各自积极入局。像诺华和拜耳这类MNC已经开始深度参与核药领域。特别是诺华，经过几年布局，已然成为核药领域的领跑者。 诺华的高举高打 诺华是近几年核药领域动作最大的MNC，到了2024年，他的脚步依然没有慢下来。 2024年4月底，诺华与PeptiDream签署了一项价值总价值约29亿美元的合作协议（包含1.8亿美元预付款，27.1亿美元里程碑以及一定比例的销售分成），共同开发多款大环肽靶向偶联核药。这是两家公司2019年达成环肽PDC合作之后又一次牵手。 作为核药龙头，诺华的治疗性RDC药物也被视为ADC之后的热门偶联药物方向之一，而将其与环肽结合，或许会是RDC之后又一次成功的迭代。 紧接着在5月2日，诺华宣布收购Mariana Oncology，以加强放射性配体疗法的布局。根据协议条款，诺华将支付10亿美元预付款，并在完成预定里程碑后再支付7.5亿美元。 Mariana Oncology成立于2021年，聚焦开发靶向肽核药，其核心资产MC-339是一种基于锕的放射性配体疗法，正在研究用于治疗小细胞肺癌，其靶点并未披露。此次收购后，诺华不仅获得了Mariana Oncology的配体发现平台，还获得了放射偶联平台，能利用α和β放射性核素满足不同的治疗需求。 可以看到诺华在核药的布局已经开始向下一代渗透。之所以诺华有这样的底气，来自其核药商业化的回报。 诺华整体收购核药企业建设核药能力，据公开信息整理 2017年，诺华以39亿美元收购了Advanced Accelerator Applications（AAA），从而获得了用于治疗生长抑素受体（SSTR）阳性的胃肠胰腺神经内分泌肿瘤（GEP-NETs）的Lutathera。 第二年，诺华首款RDC药物Lutathera便获得FDA批准上市，时至2023年，该药销售额达6.05亿美元，同比增长28%。今年上半年Lutathera以16%的增速实现收入3.44亿美元。 2018年，诺华以21亿美元收购Endocyte，进一步得到了治疗转移性去势抵抗性前列腺癌（mCRPC）的放射配体疗法Pluvicto，其后于2022年获批上市。 上市当年，Pluvicto即实现收入2.7亿美元，2023年继续放量，全年销售额9.8亿美元，同比增长超260%，成为全球年销售额最高的放射性治疗药物。今年上半年，Pluvicto以45%的增速实现收入6.55亿美元，今年大概率能突破10亿美元大关。表现如此抢眼，诺华还在推进Pluvicto用于更前线的治疗方案，及拓宽适用人群。 两款RDC药物商业化的成功，让诺华开始持续下注核药。 全面出击，扩充管线 消化了两家公司的资源，诺华已经拥有评估核药的能力，开始收购产品权益。 这段时间，诺华将目光瞄向处于研发早期的产品，既降低了交易金额，还能获得不同的辐射粒子、不同的靶点以及不同适应症。比如通过对于几款处于临床1/2期产品权益的收购，获得了一系列FAP靶点产品，有效拓展了FAP高表达的瘤种。 诺华部分产品权益收购，根据公开信息整理 通过检索Clinicaltrials，发现41项有关FAP靶点放射性药物的临床试验，由企业申请的共有6项，其中3项归属为诺华所有（NCT04939610、NCT05262855和NCT05641896），适应症分别为实体瘤、胰腺导管癌和胃肠道肿瘤。 诺华于2021年7月开启的1项关于Ga-68 FAP-2286和Lu-177 FAP-2286诊疗一体化的临床1/2期试验，是全球首个发起FAP注册临床试验的企业，其他企业启动时间要比诺华晚2年多。也就是说，如果未来3年，诺华的FAP靶向放射性药物成功陆续上市，不仅能带来新的增长曲线，同时还无人能正面竞争。 接下来，诺华开始尝试与其他企业进行战略合作开发。特别是在2021年后，诺华希望通过新的平台技术，改善核药负责靶向部分的分子性能，包括分子量小、穿透性强、亲和力高、靶向性强、体内滞留时间长等，来提高核药疗效和安全性，是核药更贴近临床需求。 此外，诺华也有参与投资核药研发企业，例如通过投资Aktis Oncology可深度孵化a粒子标记技术平台。 正是有了这一系列操作，目前诺华拥有有8条核药管线，除去2个上市产品外，还有6个处于临床1期的管线。 诺华核药管线，数据源自企业财报 对于已经上市的Lutathera，诺华还在扩展胃肠胰神经内分泌肿瘤1线治疗适应症，目前处于临床3期阶段；扩展儿童适应症、胶质母细胞瘤适应症和广泛期小细胞肺癌1线治疗适应症都处于临床2期阶段。 除了积极拓展已上市核药的适应症外，诺华也在开发LU-177标记不同靶点的放射性治疗药物，如胃泌素释放肽受体（GRPR） -NeoB、成纤维细胞活化蛋白（FAP）、整合素α-v、β-3/5。新的靶点能在多种恶性肿瘤中异常高表达,如乳腺、前列腺、胰腺、肺和中枢神经系统，且均以诊疗一体化策略进行开发。值得注意的是，除诺华外，其余各大MNC或是核药企业也在积极布局Lu-177标记的放射性治疗药物，只是他们的靶点并无明显创新。 诺华Lu-177标记新靶点药物临床试验汇总，数据源自Clinicaltrials 另一款已经上市的Pluvicto，靶点为PSMA。诺华同步开展了3项3期临床试验，均为前列腺癌，通过不同联合治疗方案，以及治疗前移到1线，前列腺癌的分型（少转移性前列腺癌），预计未来几年适应人群范围还将持续扩宽。 AAA802和AAA817这两个同样靶向PSMA的药物则展现出了诺布布局的前瞻性。 以上市的两款RDC药物为例，从药物结构上来看两款药物的核素均为Lu-177，能够产生β粒子射线，半衰期接近一周，适合小体积的肿瘤和转移灶的清除。有它们珠玉在前，RDC的研发也多集中在β核素Lu-177上。可随着研发的深入，药企也开始寻求布局创新核素，α核素开始走向前台。 在α核素中，Ac-225被认为最具前景。因其半衰期达9.9天，长于Lu-177的6.647天，生产、治疗时间更为充足，并且基于其释放的α粒子的特性，结合Ac-225开发的药物，有效性和安全性方面在理论上会比Lu-177更有优势。 不只是诺华，多家MNC都围绕Ac-225做了布局。 包括诺华17.5亿美元收购的Mariana、礼来14亿美元收购的Point pharma、BMS41亿美金收购的Rayzebio以及阿斯利康20亿美元收购的Fusion，它们旗下均有基于Ac-225开发的管线。频繁的交易也意味着，未来基于Ac-225的产品将是一个重要竞争领域。 考虑到核药在研发、临床、生产和使用等环节都受到严格监管。诺华在核药领域的先发优势还将持续一段时间。 MNC争相布局 让诺华一家独美，显然是其他MNC不愿看到的，核药赛道已经成为MNC的必争之地。 核药商业化之路存在极高壁垒，包括成熟、完备的核药上下游产业链，以及生产、运输等多个环节都需要大量的资金投入。对于核药Biotech来说，想自己走通这条路，难度极大，卖给财大气粗的MNC或许是更好的选择。而通过并购、合作切入新赛道也是MNC的常规操作。 以同样深耕多年核药领域的拜耳为例，尽管早在2013年，拜耳研发的镭-233药物Xofigo便获批上市用于治疗前列腺癌。但此后拜耳还是陆续通过收购Algeta、Noria和PSMA Therapeutics等公司，来加强其在核药领域的研发和市场影响力。 通过这些收购，拜耳不仅获得了基于锕-225和一种靶向前列腺特异性小分子抗原（PSMA）差异性α放射性核素疗法的专有权。还扩大了拜耳现有的肿瘤靶向α疗法（TAT）产品组合。此后在2023年5月，拜耳与Bicycle Therapeutics plc达成一项战略合作，共同开发多个双环肽靶向放射偶联药物。 其他MNC如阿斯利康、罗氏和礼来等也通过股权投资、技术引进等方式积极进入核药领域。如礼来在2023年10月宣布收购POINT Biopharma，获得了包括PNT2002和PNT2031在内的多款处于临床后期的核药物。 2023年12月，BMS以41亿美金收购成立仅三年多的核药公司RayzeBio，将核药市场推向新的高潮。2024年3月，阿斯利康宣布收购Fusion Pharmaceuticals，获得了基于同位素锕（actinium）的放射偶联药物管线，以及其他相关研发与生产设施。 罗氏和默沙东在核药领域的布局主要是合作。例如默沙东早在2021年就与Fusion达成合作，主要是评估核药与K药的联合疗法；2023年3月，默沙东又与Ratio Therapeuticsd合作推进核药研发。罗氏则通过在2023年9月与PeptiDream达成一项超10亿美金核药研发合作进入核药领域。 阿斯利康在今年3月用24亿美元收购Fusion Pharmaceuticals入局核药，但早在2020年，阿斯利康便与Fusion达成开发和商业化下一代α核素放射性药物和治疗癌症联合疗法的合作。2023年4月，Fusion宣布其新药IND申报获得受理，将携手阿斯利康共同开发。那么此次的收购也就顺理成章了。 从阿斯利康的角度来看，Fusion也颇具价值。首先，它拥有的α核素平台和较为领先的产品管线。Fusion的225Ac-PSMA虽然进度并非靠前，但也算第一梯队。其次便是Fusion特殊的Linker设计平台，可以减少未结合的药物分子在体内的循环，从而增加安全性。Fusion可以通过该平台源源不断地利用经验证的前体来产生FPI-2068这样的组合分子，使得临床候选药物的验证性更具优势。最后便是其Ac-225的生产以及CMC能力。 通过并购完成对供应链和生产配送能力的建设成为MNC入局的固定打法。当然，核药自身的属性也使得核药Biotech们被MNC收购是最佳的选择之一。毕竟，核药的商业化困难重重。 MNC核药如何落地国内市场 即便是诺华，也在核药的商业化上遭遇过挑战。 中国同位素与辐射行业协会预计2025年，国内放射性药物市场规模将达到93亿元人民币，到2030年，市场规模将进一步增加至260亿元人民币。面对这样一个市场，诺华自然不会放弃。 根据CDE官网的信息，诺华自2000年起，便着手在国内准备启动核药的研发。根据临床试验的申请可以看出在国内市场的研发策略也是保持了诊疗一体化、适应症扩展及治疗前移。 值得注意的是，诺华安排进入国内临床开发的仅有标记Ga-68的放射性诊断药物，以及标记LU-177的放射性治疗药物。直到2023年，因全球同步开发策略，诺华才将诊疗一体化的NeoB引入。 不仅只有临床，为配合Pluvicto在国内获批上市，诺华做了不少准备。 由于Pluvicto的有效期从工厂包装好开始计时只有5天（Lutathera只有3天），因此在目标市场建厂生产成为刚需。为此，诺华在中国投资设立了一家全新的放射性药物生产基地，确保供应能覆盖中国及周边地区。生产基地位于浙江省嘉兴市海盐县核技术应用（同位素）产业园，投资总额预计超过6亿元人民币，计划在2026年底投入生产。 此外，诺华中国将在现有乳腺癌团队、血液肿瘤团队、肺癌和实体瘤管线团队的基础上，新组建放射配体疗法团队，加速国内对创新型放射配体产品的引入，以尽快触达国内患者。 诺华CEO曾在JPM 2024上明确表示了对于核药价值的认可和长期投入，相信在未来几年核药带来的营业收入将大幅度增加，核药收入将占其年度总营业收入极大比重。 随着越来越多MNC的入局，核药研发进程将进一步加快，也推动了医药行业在肿瘤治疗领域的创新。随着越来越多的药企加入，核药赛道正迎来前所未有的繁荣期，未来随着越来越多核药的上市和产业链的完善，核药势必能成长为新一代癌症主流疗法。至于谁能率先冲线，不仅取决于各自的研发能力和商业化决策，还要看谁能更好地满足临床需求和患者利益。 * 参考资料： 《nature》The radiopharmaceutical renaissance: radiating hope in cancer therapy doi.org/10.1038/d43747-024-00014-w 国家核安全局《2030年→260亿！国内放射性药物市场规模持续扩增》 *封面图片来源：123rf 如果您认同文章中的观点、信息，或想进一步讨论，请与我们联系；也可加入动脉网行业社群，结交更多志同道合的好友。 近 期 推 荐 声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。 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As far as cancer treatments go, radiopharmaceuticals are conceptually simple. After all, radioactive isotopes are very good at killing cancer cells. And as targeting technology improves, large pharma companies are paying closer attention to the drug field and the many smaller biotechnology firms within it.This radio-renaissance belies the long history of radiation-based drugs, the idea for which has been around for more than half a century, said Jack Hoppin, CEO of Ratio Therapeutics, one of those small biotechs.Its not a novel concept to put a radioisotope into patients, Hoppin said, describing research into the radioisotope iodine-131 in the 1950s.Decades later in the early 2000s, GSKs Bexxar and Idec Pharmaceuticals Zevalin both won approvals to treat lymphoma, but their use never took off due to logistical and other issues. While radioisotopes became commonplace in diagnostic imaging, the current boom in radiopharmaceuticals was brought on by two drugs now owned by Novartis: Lutathera for neuroendocrine tumors and Pluvicto for prostate cancer.There have been a couple other successes in the space, but those are the two driving forces that caught everyones eye, said Hoppin. When a buyer like Novartis steps in and starts building infrastructure, and oncologists are willing to prescribe and treat directly with these drugs, it builds momentum.Ratio is still early in its own development journey. But backed by another pharma giant, Bristol Myers Squibb, the company has a front row seat to the fields rapid expansion.I think youll see these drugs evolve in the way that antibody-drug conjugates have said Hoppin. It took time to adopt and come to fruition, but were now in an era where companies are looking for fit-for-purpose molecules for radioligand therapy and the characteristics required to be successful.Merging fieldsOne of the challenges in developing radiopharmaceuticals is balancing the drugs potency with their safety. The isotope the drugs contain must be linked securely enough to a targeting compound that it reaches the target tumors, but loosely enough that it can be deposited upon arrival.To get that balance right requires more than just biology and chemistry, said Hoppin, who holds a Ph.D. in mathematics. For example, understanding the way radioactive isotopes actinium-225 in Ratios case populate into a tumor is as much a math problem as it is biological.People in pharmaceutical sciences underestimate nuclear medicine, and people in nuclear medicine underestimate pharmaceutical sciences, said Hoppin. We try to acknowledge that youre only as good as the weakest disciplinarian within your group.Ratio uses actinium-225 with a combination of targeting and linking platforms to ensure a calculated dose for its treatments, one of which is close to entering Phase 1 testing.While biotechnology advances can come in seemingly overnight breakthroughs, Hopping credits the steady accumulation of better targets and biomarkers for the growth in therapeutic radiopharmaceuticals.There wasnt a clear-cut smoking gun that changed the market, he said. [It was] more an evolution of medicinal chemistry and biomarker technology to image these agents faster and more quantitatively.Building a marketRatio is one of more than a dozen small- to mid-sized startups exploring radiopharmaceuticals. Acquisitions by large pharma companies have boosted the field, encouraging the formation of new companies and funding for those already established.Bristol Myers Squibb announced a $4.1 billion acquisition of RayzeBio at the end of last year. That same week, Eli Lilly completed a $1.4 billion purchase of Point Biopharma. Both companies have radiopharmaceutical candidates in clinical trials.Then this year, AstraZeneca bought Fusion Pharmaceuticals for $2.4 billion, continuing the dealmaking trend. There were 86 licensing, partnering or acquisition deals in the radiopharmaceuticals field over the last five years, according to a Nature report, with the number of deals nearly tripling between 2021 and 2022.There are still challenges in the field, as Hoppin can attest, from manufacturing of radioactive materials to supply chain and storage. But the future looks bright.Some of these things cant be instantly solved, but looking out a decade, there are going to be multiple approvals and really exciting times, Hoppin said. '

VALENCIA, Calif., June 07, 2024 (GLOBE NEWSWIRE) -- Nusano, Inc., a physics company transforming the production of medical radioisotopes, today announced industry veteran D. Scott Holbrook as chairman of its board. Holbrook is the co-founder of Invivo Molecular Imaging, and currently serves as the general manager and chief strategy officer for Pharmalogic, a leading contract development and manufacturing organization specializing in novel diagnostic imaging and therapeutic radiopharmaceuticals for the treatment of cancers. He has served on Nusano’s board since September 2022. Holbrook brings over 25 years of experience growing companies in biotech and radiopharmaceuticals to the role. His experience will be critical as Nusano begins commercialization and scale-up of its proprietary medical radioisotope production technologies. “Many highly promising cancer treatments in development are in desperate need of a reliable supply of medical radioisotopes,” said Holbrook. “Nusano’s proprietary technologies are poised to make many of these critical components available and abundant in ways no other production method can. It’s an honor to have this opportunity to lead the board and help advance an exciting new era in radiotherapeutics.” Chris Lowe, CEO of Nusano, commented, “Scott has been an invaluable member of our board and is a passionate advocate for patients. As our production capacity comes online, his strategic insights and experience will help ensure our customer needs are met in a timely and reliable manner.” Radioisotopes are essential components in the active pharmaceutical ingredients (API) of a category of new and emerging cancer therapies, known as radiotherapeutics. Existing supply chains for these treatment-enabling resources are often strained, posing a risk to patient care, clinical trials, and ongoing drug development. Nusano is working to stabilize supply chains and enable innovation by bringing new sources of radioisotopes to commercial markets. The company expects to begin producing and delivering commercial-scale quantities of lutetitum-177 in Q1 2025 and actinium-225 in H2 2025. Nusano’s first-of-its-kind production facility opens Q1 2025 in West Valley City, Utah. At full scale it will be capable of producing more than 25 radioisotopes of interest to medicine, and the simultaneous production of up to 12 different radioisotopes. In addition to his roles at Nusano and PharmaLogic, Holbrook serves as an adjunct professor in the Department of Radiology at the University of Utah, and on the board of Ratio Therapeutics. He holds a Master of Science in Molecular Imaging and Therapy from Regis College and a Bachelor of Science in Clinical Nuclear Medicine from Wheeling University. About NusanoNusano is a privately held physics company committed to bringing stability and innovation to the rapidly emerging and critically undersupplied medical radioisotopes market. Nusano’s proprietary ion source is smaller and more efficient than existing production methods. This results in significantly greater yields and allows for the simultaneous manufacturing of multiple radioisotopes. Nusano’s technologies will supply the fight against cancer and support diagnostic and therapeutic radiopharmaceutical development. The company’s state-of-the-art production facility opens Q1 2025 in West Valley City, Utah. For more, please visit www.nusano.com. Contacts: Media: Scott Larrivee, Nusano, 608-345-6629, scott.larrivee@nusano.comInvestor Relations: Joyce Allaire, LifeSci Advisors, LLC, 212-915-2569, jallaire@lifesciadvisors.com