RYZ-101

iStock, Love Employee While Novartis and Bayer got there first, AstraZeneca, Bristol Myers Squibb and Eli Lilly are all vying to bring their radiopharmaceutical assets to a market projected to be worth over $13 billion by 2033. When the FDA approved a small and peculiar eight-amino acid peptide therapy in 2018, it also signed off on a field that today provides a precise and personalized approach to treating cancer. Novartis’ Lutathera belongs to a class called radiopharmaceuticals, which combines a radioactive substance and a biological agent into one therapeutic molecule. Lutathera carries lutetium-177, a beta-emitting isotope of lutetium that releases high-energy radiation as it degrades, in turn damaging a cancer cell’s DNA and ultimately leading to its death. Meanwhile, the drug’s eight-residue backbone allows it to specifically home in on subtype 2 somatostatin receptors, proteins typically highly expressed on specific types of cancer cells. This specific structure gives Lutathera—and radiotherapies more broadly—their characteristic precision. Radiopharmaceutical drugs “can generally shrink tumors effectively without causing much side effects,” Andrew Tsai, an analyst at Jefferies, told BioSpace in an email. The use of radioisotopes gives this modality its marked efficacy, Tsai continued, adding that these treatments might also lead to a more durable, longer-lasting therapy. “Lethality of radiation on cancer is robust, and there is no resistance mechanism to the modality,” he explained. Of course, the use of radioactive agents, no matter how targeted, is still bound to cause some toxicity. According to Tsai, radiotherapies can lead to the accumulation of radiation in various organs, which “could limit the dosing potential” of the modality. There is also a limit to how precise radiopharmaceuticals can get, and they still sometimes lead to unintended off-target side effects such as dry mouth and alopecia. On a more practical level, supply constraints also pose a roadblock to radiopharmaceuticals. “Having access to radioisotope[s] has been rate limiting in many instances even for clinical trials,” Tsai said. Another barrier, he continued, is that the practice has yet to penetrate sufficiently into current medical practice; both patients and physicians remain uninformed or uncomfortable about the tech, and there is a need to improve their awareness. Here, BioSpace looks at the current state of radiopharmaceuticals through five leading players—Novartis, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Bayer—including their strategic moves and key upcoming milestones in a space projected to be worth more than $13 billion by 2033. Novartis Seeks to Maintain Radiopharma Leadership Radiopharma assets: Lutathera, Pluvicto Novartis is the clear frontrunner in the radiopharmaceutical race. The Swiss drugmaker already has two commercial products on the market: Lutathera, indicated for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), and Pluvicto, for metastatic castration-resistant prostate cancer (mCRPC). Compared with its competitors, Novartis has also fleshed out “industry-leading radioligand research and production sites” globally, Geoff Towle, vice president of the company’s radioligand therapy solid tumor strategy, told BioSpace in an email. Despite enjoying a comfortable lead, Novartis continues to strengthen its radiopharma portfolio. In May 2024, the company paid $1 billion to acquire Mariana Oncology and its promising pipeline, anchored by MC-339, an actinium-based therapy being studied in small cell lung cancer (SCLC). Novartis also recently launched two pivotal trials for the next-generation radiotherapy AAA817, which is under development for prostate cancer, Towle shared. Like Pluvicto, AAA817 targets the prostate-specific membrane antigen (PSMA) but instead carries an actinium-based payload, which could deliver higher potency . Aside from building out the pipeline, Novartis is also seeking to expand the indications for its current products. Pluvicto, for instance, is currently under review by the FDA for use in earlier-stage mCRPC, with a regulatory verdict expected in the first half of 2025 , Towle said. This approval, if granted, would allow the use of Pluvicto ahead of chemotherapy and would highlight the “potential for radioligand therapy to become an established pillar of cancer care,” he added. These strategic moves, according to Towle, place the company in a strong position to “realize the $10 billion business potential of our candidates in clinical trials or pre-clinical trials,” and bring radioligand therapies beyond prostate and neuroendocrine tumors to other areas of high unmet patient need, including breast and lung cancer. AstraZeneca Zeroes in on Radioconjugates Radiopharma assets: FPI-2265, AZD2068 AstraZeneca bought entry into the radiopharma market in March 2024, with the up to $2.4 billion acquisition of Fusion Pharmaceuticals. Despite being a relative newcomer to the space, AstraZeneca has set its sights high. In a company presentation last month, the pharma announced that radioconjugates are expected to be a strong driver of its business by 2030 and beyond. “Our aim is to build a substantial radioconjugate portfolio to offer treatment options for patients with a broad range of tumor types,” Puja Sapra, AstraZeneca’s senior vice president for biologics engineering and oncology target discovery, told BioSpace in an email. In particular, the pharma envisions that radioconjugates will complement existing radiation therapy and help reach other cancer types that have been difficult to treat. AstraZeneca’s radiopharma pipeline is anchored by FPI-2265—the centerpiece of the Fusion acquisition—which consists of a small molecule drug that targets PSMA and carries an actinium-225 radioisotope that can inflict irreparable damage to cancer cells. FPI-2265 is being assessed in the Phase II AlphaBreak study in patients with PSMA-positive mCRPC, with a readout expected in the second half of 2025, according to Sapra. AstraZeneca is also working on AZD2068, another radioconjugate from Fusion, designed to target cells expressing the EGFR and cMET markers. The asset is currently in a Phase I study for advanced solid tumors. Findings are expected in 2026 at the earliest, according to the pharma’s latest pipeline document. Aside from its pipeline, AstraZeneca is also working on “molecular imaging and computation pathology,” which according to Sapra would “enhance the delivery and monitoring” of radioconjugates. The end goal, she continued, is to “deliver the right treatment to the right patient.” BMS Leads the Way in Actinium-Based Radiotherapies Radiopharma assets: RYZ-101, RYZ-801 A few months ahead of AstraZeneca, Bristol Myers Squibb made a major radiopharma play in December 2023 with the acquisition of RayzeBio and its actinium-225-based platform for $4.1 billion. “RayzeBio is pioneering the use of Actinium-225,” which is an alpha-emitting radioisotope, Ben Hickey, the company’s president under BMS, told BioSpace in an email. “We believe alpha-emitting isotopes represent the next generation of therapeutic radionucleotides due to their higher potency as compared to beta-emitting isotopes.” Novartis’ Lutathera and Pluvicto carry beta-emitting lutetium-177. With the RayzeBio acquisition, BMS gained ownership of the biotech’s lead asset RYZ-101, which targets somatostatin receptor type 2, a protein commonly expressed on certain solid tumors. BMS is running three clinical trials for RYZ-101: A Phase III study for GEP-NETs and Phase I studies in unresectable metastatic breast cancer and extensive-stage SCLC. The SCLC study will read out later this year , while pivotal data for GEP-NETs are expected in 2026, according to Hickey. “If successful, we believe RYZ101 could be the first [actinium-255-based radiopharmaceutical therapy] approved In the U.S.” BMS is also advancing RYZ-801 , which consists of a proprietary peptide bound to an actinium-225 radioactive payload. RYZ-801, which targets the GPC3 protein, entered the clinic late last year for hepatocellular carcinoma, with enrollment currently ongoing, according to Hickey. Aside from these two clinical assets, the acquisition of RayzeBio gave BMS what Hickey called an “IND-generating engine” that can produce “several therapeutic candidates in the coming years.” BMS currently has several preclinical programs ongoing, he said. Beyond beefing up its radiopharma pipeline, BMS is also building up manufacturing capabilities. Hickey said the pharma’s facility in Indianapolis “is now fully operational” and can contribute to clinical supply, while BMS works to ramp up the site to support commercial-scale operations. Eli Lilly Enters Radiopharma Space With Dealmaking Flurry Radiopharma asset: PNT2001 and PNT2002 Ahead of both BMS and AstraZeneca, Lilly entered the radiopharma arena in October 2023 with $1.4 billion to acquire Point Biopharma—a transaction that formally closed in December that year. Less than a year later, in May 2024, Lilly doubled down on radiopharma with an agreement with Aktis Oncology worth up to $1.1 billion. The deal gave Lilly access to the biotech’s proprietary discovery engine to develop novel radiotherapeutic assets against certain cancer targets. But Lilly wasn’t done. In July 2024, the company entered into another strategic alliance , this time with Radionetics Oncology, for $140 million upfront. The partners will work on radiotherapies targeting small-molecule G-protein coupled receptors for the treatment of various solid tumors. Under the deal, Lilly also has the exclusive right to acquire Radionetics for $1 billion. From the Point acquisition, Lilly gained ownership of the biotech’s lead asset PNT2002, a PSMA-targeted lutetium-177-based therapy being proposed for patients with mCRPC whose disease has progressed after hormonal treatment. A Phase III readout in December 2023 for PNT2002 was disappointing : The asset reduced the risk of death or disease progression by 29% versus androgen receptor blockage—an effect that met statistical significance but fell below what analysts had hoped for. Regulatory filings for PNT2002 are “pending,” according to Jefferies’ Tsai. Lilly has other radiopharma bets in the clinic, including PNT2001, which targets the PSMA protein and carries a 225-actinium radioisotope payload. The asset is currently in Phase I development for prostate cancer. According to a Feb. 7 Jefferies note, Lilly also has a preclinical radiopharma candidate that uses 225-actinium. Another, PNT2003, delivers lutetium-177 and targets the somatostatin receptor to address GEP-NETs. Bayer Builds Radiopharma Pipeline Beyond Xofigo Radiopharma assets: Xofigo, 225Ac-Pelgifatamab, 225Ac-PSMA-Trillium Aside from Novartis, the only other company on this list with an FDA-approved radiopharma asset is Bayer. Xofigo , a radium-223 dichloride radioactive drug, was cleared by the FDA in 2013 for the treatment of castration-resistant prostate cancer with symptomatic bone metastases and with no known visceral metastatic disease. Unlike Novartis’ Lutathera and Pluvicto, however, Xofigo does not include a targeting moiety. Instead, the drug takes advantage of radium’s chemistry, which allows it to bind to bone minerals, in turn helping localize the drug to sites of high bone turnover. Xofigo’s market performance has been underwhelming, peaking at €408 million in 2017 . Bayer did not report specific sales for Xofigo last year. But the pharma is attempting to carve out a space in today’s radiopharma space, inking a strategic collaboration with Bicycle Therapeutics in May 2023. For $45 million upfront and up to $1.7 billion in milestones, Bayer gained access to Bicycle’s proprietary peptides, which it will use to develop targeted radiotherapies for several undisclosed cancer targets. As per its pipeline page , Bayer has at least two clinical-stage radiopharmaceutical therapies in development: 225Ac-Pelgifatamab and 225Ac-PSMA-Trillium, both actinium-based candidates in early-stage studies for advanced prostate cancer.

PREFACE 前言 2023年之前，核药还只是诺华和拜耳两家MNC重点谋划的方向，但在随后的两年，诸多MNC开始通过一系列合作、并购、投资强势入局，核药赛道热度不断飙升。 因此在JPM 2025上，各大MNC和biotech的核药布局与进展值得关注。 01 拜耳，核药领域先行者 拜耳作为较早布局核药赛道的MNC，早在2009年就与Algeta合作开发Xofigo，并于2013年获批上市，用于治疗晚期骨转移型去势抵抗性前列腺癌。 Xofigo上市后，销售额在2017年达到峰值（4.08亿欧元），后续开始逐年下滑。尽管Xofigo并没有如愿成为一款重磅炸弹，但是拜耳也从未停止对于核药赛道新疗法的布局。 根据拜耳本次JPM上的演讲PPT，2024年前三季度放射学板块整理营收达到15亿欧元，同比增长7%，表现亮眼。 在研管线方面，目前拜耳有两款核药正处于临床1期阶段，分别是BAY 3546828和BAY 3563254，从核素的选择上可以看出拜耳倾向于α核素，两款核药采用的核素均为225AC。 02 诺华，核药赛道王者 诺华2024年Q3收入同比增长10%，核心营业利润同比增长20%，2024年内三次上调收入预期，这样的表现在一众MNC中已是非常亮眼的存在。 如此结果得益于诺华多点开花、均衡增长的策略，其中在核药赛道的落子便是诺华迈出的关键一步，目前诺华手握两款RDC（核素偶联药物）Lutathera和Pluvicto，2024年前三季度分别贡献了5.34亿美元以及10.41亿美元销售额。 根据诺华在本次JPM上的演讲PPT，目前支撑诺华创新研发的共有五大技术平台，RLT（放射性配体疗法）便是其中之一，主要在肿瘤和免疫领域发力。 重磅RDC药物Pluvicto是诺华未来业绩增长的核心之一，预计销售峰值将超过50亿美元。在适应症拓展方面，预计在2025年获批pre-taxane进军1L mCRPC，mHSPC的临床数据也预计将在2025年读出。 此外诺华还储备了多款核药管钱。如靶向GRPR的Lu-NeoB，目前正在探索乳腺癌等适应症，预计将在2026年读出数据；FXX489（177Lu-NNS309），靶点尚未公布；采用α核素以及靶向PSMA的Ac-PSMA-617和Ac-PSMA-R2，正在探索前列腺癌适应症的潜力，前者预计在2025H1进入临床3期，后者预计在2026年读出数据；以及AAA614（177Lu-FAP-2286），目前已经处于治疗实体瘤的2期临床，用于诊断的68Ga-FAP-2286也在同步开发中。 03 BMS：重金杀入核药领域 随着Pluvicto的起势，BMS也开始入局核药。2023年末以约250%的溢价收购了RayzeBio，从而囊获了RYZ101、RYZ801等创新靶向核药，以及GMP工厂和技术平台。 但BMS这笔收购后续研发并不太顺利，由于核素的短缺，BMS在2024年6月初暂停了RYZ101在研3期临床试验的患者入组，后续在解决了核素的供应问题后，BMS也是重启了这项临床试验。 根据BMS在本次JPM上的演讲PPT，在重金入局后，核药已经成为了BMS肿瘤板块四大重点投资方向之一。 BMS预计将在2025年读出RYZ101 1L治疗ES-SCLC的早期数据，在2026年读出RYZ101 2L+治疗GRP-NETs的注册临床试验数据。 此外，RYZ801目前正在探索治疗HCC适应症，并且在本次JPM召开前夕，BMS从艾博兹医药处，重新获取了RYZ801在大中华区开发和商业化的独家权力。 04 阿斯利康： 从合作到收购，切入核药赛道 阿斯利康在正式切入核药赛道前，先通过合作进行了试水。2020年11月，阿斯利康与Fusion Pharmaceuticals达成了一笔总金额为4500万美元的合作，开发下一代基于α粒子的核药。 通过合作，阿斯利康看到了合作伙伴Fusion旗下Fast-Clear linker的潜力，因而在核药升温之际，以最直接的方式，24亿美元收购Fusion，正式切入核药赛道，在获得技术平台的同时，还囊获了FPI-2265、FPI-1434、FPI-2068和FPI-2059四款在研核药。 在收购Fusion后的不久，阿斯利康再次投资了核药CDMO公司Nucleus RadioPharma，开始全链条布局核药。 根据阿斯利康在本次JPM上的演讲PPT，RDC和ADC在未来将替代全身性放化疗，成为完成“2030愿景（2030年营收增至800亿美元）”的关键一部分。 目前AZ共有两款重点研发的核药FPI-2265和AZD2068。FPI-2265是一款采用α核素Ac-225的靶向PSMA的RDC，目前正在探索mCRPC适应症，已经启动2/3期临床。AZD2068（FPI-2068）同样采用的是α核素Ac-225，靶向c-MET和EGFR，目前处于临床1期。 05 Bicycle：拜耳、诺华的合作伙伴 除了多家MNC在本次JPM上分享了核药的内容外，还有一家与MNC达成深度合作的核药biotech也分享了公司的谋篇布局——专注于开发双环肽的Bicycle therapeutics（由于Bicycle没有公开JPM演讲PPT，以下截图来自Bicycle在JPM召开前一日公开的deck）。 双环肽分子集抗体、小分子药物及肽类的特性于一身，具有与抗体类似的亲和性和精确的靶向特异性；同时，由于它们分子量较小，使得其能够快速深入地渗透组织，从而实现从组织内部靶向病灶；其肽类的性质则提供了“可调控”的药物动力学半衰期和肾脏清除途径，从而避免了其他药物形式中常见的肝脏和胃肠道毒性。 基于以上特性，Bicycle获得了诸多MNC的青睐，包括与诺华、拜耳在内的MNC达成了开发基于双环肽核药的合作。 在研发管线方面，Bicycle布局了多款双环肽放射性偶联药物（BRC）。 Bicycle此前公布了MT1-MMP BRC的首个人体成像数据，验证了MT1-MMP作为抗肿瘤新靶点的潜力，以及双环肽分子将放射性同位素递送至肿瘤的能力。目前，Bicycle已经选择了将EphA2作为第二个BRC药物靶点。