Phase 1/1b Single Arm, Open-label Trial of Theranostic Pair RYZ811 (diagnostic) and RYZ801 (therapeutic) to Identify and Treat Subjects with GPC3+ Unresectable Hepatocellular Carcinoma (HCC)

A single arm, open-label Phase 1/1b study of the theranostic pair RYZ811 (diagnostic) and RYZ801 (therapeutic) to identify and treat subjects with GPC3+ unresectable HCC

开始日期2024-12-01

申办/合作机构

Rayzebio, Inc.初创企业

NCT06411301 / Not yet recruiting临床1期IIT

A Phase I Study to Assess the Tolerability of 225Ac-DOTATATE in Patients With Refractory and Relapsing Multiple Myeloma Expressing Somatostatin Receptors

This study aims to determine the safety and the recommended phase II dose of RYZ101 (actinium-225 labelled DOTA-octreotate (225Ac-DOTATATE)) in participants with refractory and relapsing multiple myeloma (MM) that have received at least 3 prior lines of myeloma therapy. Participants will be selected based on somatostatin receptor (SSTR) positivity assessed by gallium-68 labelled DOTA-octreotate (68Ga-DOTATATE) PET/CT. The response to 225Ac-DOTATATE therapy will also be assessed in the target study population.

开始日期2024-10-01

申办/合作机构

Jules Bordet Institute

[+1]

NCT06590857 / Recruiting临床1/2期

Phase 1b/2 Open-label Trial of 225Ac-DOTATATE (RYZ101) Alone and in Combination with Pembrolizumab in Subjects with Estrogen Receptor-positive (ER+), Human Epidermal Growth Factor Receptor 2 (HER2)-negative, Locally Advanced and Unresectable or Metastatic Breast Cancer Expressing Somatostatin Receptors (SSTRs) and Progressed After Antibody-drug Conjugates And/or Chemotherapy (TRACY-1)

Phase 1b/2 open-label trial of 225Ac-DOTATATE (RYZ101) alone and with pembrolizumab in subjects with ER+, HER2-negative unresectable or metastatic breast cancer expressing SSTRs.

开始日期2024-07-19

申办/合作机构

Rayzebio, Inc.初创企业

100 项与 Rayzebio, Inc. 相关的临床结果

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0 项与 Rayzebio, Inc. 相关的专利（医药）

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项与 Rayzebio, Inc. 相关的文献（医药）

2024-04-01·Journal of nuclear medicine : official publication, Society of Nuclear Medicine

Peptide Binder to Glypican-3 as a Theranostic Agent for Hepatocellular Carcinoma

Article

作者: Richardson, Samantha ; Ehara, Takeru ; Yanagida, Hayato ; Clift, Renee ; Han, Guangzhou ; Kim, Daniel ; Song, Kenneth ; Noncovich, Alain ; Horton, Steven ; Miller, Terra ; Bhat, Abhijit ; Lin, Fanching ; Guest, Matt ; Li, Gary ; Salvador, Katrina

Glypican-3 (GPC3) is a membrane-associated glycoprotein that is significantly upregulated in hepatocellular carcinomas (HCC) with minimal to no expression in normal tissues. The differential expression of GPC3 between tumor and normal tissues provides an opportunity for targeted radiopharmaceutical therapy to treat HCC, a leading cause of cancer-related deaths worldwide. Methods: DOTA-RYZ-GPC3 (RAYZ-8009) comprises a novel macrocyclic peptide binder to GPC3, a linker, and a chelator that can be complexed with different radioisotopes. The binding affinity was determined by surface plasma resonance and radioligand binding assays. Target-mediated cellular internalization was radiometrically measured at multiple time points. In vivo biodistribution, monotherapy, and combination treatments with ¹⁷⁷Lu or ²²⁵Ac were performed on HCC xenografts. Results: RAYZ-8009 showed high binding affinity to GPC3 protein of human, mouse, canine, and cynomolgus monkey origins and no binding to other glypican family members. Potent cellular binding was confirmed in GPC3-positive HepG2 cells and was not affected by isotope switching. RAYZ-8009 achieved efficient internalization on binding to HepG2 cells. Biodistribution study of ¹⁷⁷Lu-RAYZ-8009 showed sustained tumor uptake and fast renal clearance, with minimal or no uptake in other normal tissues. Tumor-specific uptake was also demonstrated in orthotopic HCC tumors, with no uptake in surrounding liver tissue. Therapeutically, significant and durable tumor regression and survival benefit were achieved with ¹⁷⁷Lu- and ²²⁵Ac-labeled RAYZ-8009, as single agents and in combination with lenvatinib, in GPC3-positive HCC xenografts. Conclusion: Preclinical in vitro and in vivo data demonstrate the potential of RAYZ-8009 as a theranostic agent for the treatment of patients with GPC3-positive HCC.

2023-12-01·Molecular cancer therapeutics

RYZ101 (Ac-225 DOTATATE) Opportunity beyond Gastroenteropancreatic Neuroendocrine Tumors: Preclinical Efficacy in Small-Cell Lung Cancer

Article

作者: Han, Guangzhou ; Kim, Daniel ; Clift, Renee ; Lin, Fanching ; Guest, Matt ; Li, Gary ; Hwang, Eunmi ; Bischoff, Eric ; Moran, Susan

Abstract:

Overexpression of somatostatin receptors (SSTR), particularly SSTR2, is found in gastroenteropancreatic neuroendocrine tumors (GEP-NET), and subsets of other solid tumors such as small-cell lung cancer (SCLC). SCLC accounts for approximately 13% to 15% of lung cancer and lacks effective therapeutic options. IHC analysis indicates that up to 50% of SCLC tumors are SSTR2-positive, with a substantial subset showing high and homogenous expression. Peptide receptor radionuclide therapy with radiolabeled somatostatin analogue, Lu-177 DOTATATE, has been approved for GEP-NETs. Different strategies aimed at improving outcomes, such as the use of alpha-emitting radioisotopes, are currently being investigated. RYZ101 (Ac-225 DOTATATE) is comprised of the alpha-emitting radioisotope actinium-225, chemical chelator DOTA, and octreotate (TATE), a somatostatin analogue. In the cell-based competitive radioligand binding assay, RAYZ-10001-La (lanthanum surrogate for RYZ101) showed high binding affinity (Ki = 0.057 nmol/L) to human SSTR2 and >600-fold selectivity against other SSTR subtypes. RAYZ-10001-La exhibited efficient internalization to SSTR2-positive cells. In multiple SSTR2-expressing SCLC xenograft models, single-dose intravenous RYZ101 3 μCi (0.111 MBq) or 4 μCi (0.148 MBq) significantly inhibited tumor growth, with deeper responses, including sustained regression, observed in the models with higher SSTR2 levels. The antitumor effect was further enhanced when RYZ101 was combined with carboplatin and etoposide at clinically relevant doses. In summary, RYZ101 is a highly potent, alpha-emitting radiopharmaceutical agent, and preclinical data demonstrate the potential of RYZ101 for the treatment of patients with SSTR-positive cancers.

2022-06-01·Molecular imaging and biology3区 · 医学

PET Imaging of VLA-4 in a New BRAFV600E Mouse Model of Melanoma

3区 · 医学

Article

作者: Day, Kathryn E ; Nigam, Shubhanchi ; Ho, Khanh-Van ; Anderson, Carolyn J ; Storkus, Walter J ; Patel, Ravi B ; Fecek, Ronald J ; Edinger, Robert S ; Nyiranshuti, Lea ; Taylor, Jennifer L ; Gallazzi, Fabio ; Latoche, Joseph D ; Pun, Michael ; Bellavia, Michael C

PURPOSE:

Despite unprecedented responses to immune checkpoint inhibitors and targeted therapy in melanoma, a major subset of patients progresses and have few effective salvage options. We have previously demonstrated robust, selective uptake of the peptidomimetic LLP2A labeled with Cu-64 ([⁶⁴Cu]-LLP2A) for positron emission tomography (PET) imaging in subcutaneous and metastatic models of B16F10 murine melanoma. LLP2A binds with high affinity to very late antigen-4 (VLA-4, integrin α₄β₁), a transmembrane protein overexpressed in melanoma and other cancers that facilitates tumor growth and metastasis. Yet B16F10 fails to faithfully reflect human melanoma biology, as it lacks certain oncogenic driver mutations, including BRAF mutations found in ≥ 50 % of clinical specimens. Here, we evaluated the PET tracer [⁶⁴Cu]-CB-TE1A1P-PEG₄-LLP2A ([⁶⁴Cu]-LLP2A) in novel, translational BRAF^V600E mutant melanoma models differing in VLA-4 expression-BPR (VLA-4^-) and BPRα (VLA-4⁺).

PROCEDURES:

BPR cells were transduced with α₄ (CD49d) to overexpress intact cell surface VLA-4 (BPRα). The binding affinity of [⁶⁴Cu]-LLP2A to BPR and BPRα cells was determined by saturation binding assays. [⁶⁴Cu]-LLP2A internalization into B16F10, BPR, and BPRα cells was quantified via a plate-based assay. Tracer biodistribution and PET/CT imaging were evaluated in mice bearing subcutaneous BPR and BPRα tumors.

RESULTS:

[⁶⁴Cu]-LLP2A demonstrated high binding affinity to BPRα (K_d = 1.4 nM) but indeterminate binding to BPR cells. VLA-4⁺ BPRα and B16F10 displayed comparable time-dependent [⁶⁴Cu]-LLP2A internalization, whereas BPR internalization was undetectable. PET/CT showed increased tracer uptake in BPRα tumors vs. BPR tumors in vivo, which was validated by significantly greater (p < 0.0001) BPRα tumor uptake in biodistribution analyses.

CONCLUSIONS:

[⁶⁴Cu]-LLP2A discriminates BPRα (VLA-4⁺) vs. BPR (VLA-4^-) melanomas in vivo, supporting translation of these BRAF-mutated melanoma models via prospective imaging and theranostic studies. These results extend the utility of LLP2A to selectively target clinically relevant and therapy-resistant tumor variants toward its use for therapeutic patient care.

357

项与 Rayzebio, Inc. 相关的新闻（医药）

2024-11-27

·新药前沿

诺华“四面出击”，构筑“核药帝国”防护网

通过获批产品市场快速扩张、丰富的在研管线布局、积极的项目许可引进和对竞争者直接的专利诉讼，诺华正在“四面出击”，以巩固其放射性药物领域“核药帝国”地位。获批产品市场扩张诺华一直是放射性药物领域明显的领航者，该公司内部开发的前列腺癌药物Pluvicto（镥[177Lu]特昔维匹肽）和通过收购Endatory获得的神经内分泌肿瘤药物Lutathera（[177Lu]镥氧奥曲肽）分别于2018年和2022年获批上市。在2024年前9个月，Lutathera的销售额为5.34亿美元，比去年同期增长17%；而Pluvicto则实现了10.4亿美元的销售额，同比增长47%，顺利跨过了“重磅炸弹级”的门槛。随着已获批上市产品在欧美等发达国家市场应用的推广，Lutathera和Pluvicto将会为诺华带来可观的收入。与此同时，诺华也在拓展项目在更广泛的监管市场获批，如在中国，11月13 日，镥[177Lu]特昔维匹肽上市申请已获的CDE受理。研发管线储备丰富除了已获批上市Pluvicto和Lutathera适应症扩展研究外，诺华的内部管线包括多款镥177（如177Lu-NeoB、AAA604）和锕225（225Ac-PSMA-R2、225Ac-PSMA-617）有效载荷药物，后者是该公司技术平台的重点。锕225比镥177等β疗法释放更多能量，可能使其更有效地杀死肿瘤细胞。辐射源的选择是开发人员区分候选物的一种方式。靶向分子和接头技术也很重要，会影响肿瘤对有效负载的吸收以及正常组织中同位素的清除等因素。所有这些因素共同影响疗效、安全性和耐受性，并可能决定哪些候选物在竞争激烈的市场上留下来。外购不停止诺华2018年10月以超过20亿美元交易额通过收购Endatory获得的Pluvicto。自那以后，这家瑞士制药公司并没有止步，而是一直渴望扩大其在该领域的产品线，今年上半年，诺华以10亿美元收购了Mariana Oncology，并与PeptiDream达成了扩大许可协议。 11月18日，诺华还与Ratio Therapeutics达成了一项价值高达7.45亿美元的放射性药物交易，合作开发一种靶向生长抑素受体2(SSTR2)的放射治疗候选药物。专利诉讼阻击竞争对手当然，放射性药物也在引发竞争对手的垂涎。如百时美施贵宝和礼来分别在收购RayzeBio和Point Biopharma时获得了SSTR2放射性药物。Perspective Therapeutics还正在开发一种SSTR2放射性药物候选药物。其中礼来/Point的PNT2003和诺华的Lutathera都是使用β发射体镥177作为其有效负载。今年6月份，诺华与普渡研究基金会联手向美国印第安纳州南区地方法院提起的一项诉讼中，指控Point的PNT2002侵犯了其美国专利10624970。该专利于2020年授予普渡大学，随后授权给诺华子公司Endatory。通过针对PSMA阳性前列腺癌，PNT2002和Pluvicto将直接竞争。此外，诺华还在为其Lutathera遭遇仿制进行阻击。诺华起诉Point/Lantheus和Curium在某些专利到期之前制造其Lutathera的版本。 FDA接受Lantheus的PNT2003（Lutathera仿制药）申请后不久，诺华于1月份启动了诉讼工作。作为第一个提交ANDA申请，Lantheus可能有资格在美国获得180天的仿制药市场独占权。争论的焦点是美国专利10596276，根据特拉华州提交的诉状，Point/Lantheus认为该专利“无效、不可执行和/或不会被PNT2003侵犯”。该专利于2020年颁发，涉及用于诊断或治疗目的的高浓度和高化学稳定性的放射性核素疗法。该配方专利将于2038年到期。至于最近针对Curium的诉讼，10月份的诉讼是在Curium向FDA申请LutetiumLu-177dotatate（Lutathera的一种版本）新药申请之后发生的。除了'276专利之外，Curium还在挑战诺华的第10596278号和第11904027号专利。这些专利分别于2020年和2024年授予，描述了“稳定、浓缩的放射性核素复合溶液”。诺华此前曾在密苏里州（被告北美总部所在地）对Curium提起诉讼。双方最近同意自愿驳回该案，并将重点放在特拉华州作为适当地点进行诉讼。本文由「新药前沿」微信公众号根据公开资料整理编辑，欢迎个人转发至朋友圈。媒体或机构转载授权请在「新药前沿」微信公众号留言公众号名称，审核通过后开通白名单获取转载授权，转载请标识来源。免责声明：本文仅作信息交流之目的，非投资建议或者治疗方案推荐，「新药前沿」微信公众号不对任何主体因使用本文内容而导致的任何损失承担责任。限于作者水平和专业知识所限，如有谬误，欢迎指正！

并购放射疗法专利侵权

2024-11-19

·Outsourcing Pharma

C Ray Therapeutics raises $100 million to develop radiopharmaceuticals

C Ray Therapeutics has announced the completion of a series A+ financing round, which has exceeded the $100 million mark. The round was co-led by Shenzhen Capital Group and TaiLong Capital, with participation of GL Ventures, 3SBio, Guanghua Wuting among others. Headquartered in Chengdu, China, C Ray Therapeutics specializes in the development of radionuclide drug conjugates (RDCs), a drug modality consisting of a drug carrier molecule linked to a radioactive molecule. This technology enables the delivery of a radiotherapeutic payload to a specific target, preventing or reducing the potential side effects associated with systemic delivery of a radioactive compound. Radiopharmaceuticals have a wide range of applications, including cardiovascular diseases, neurological disorders, and oncology. The latter is a major area of interest for the pharmaceutical industry, where RDCs can be used for diagnostic applications as well as a therapeutic modality. Founded in late 2020, C Ray Therapeutics has rapidly established world-class facilities and expertise in R&D, production and supply chain management of radiopharmaceuticals. This includes end-to-end contract research, development and manufacturing organization (CRDMO) services for radiopharmaceuticals, from early discovery through commercial production. Innovative radiopharmaceuticals “C Ray Therapeutics has now entered a critical phase of rapid development,” stated a representative of the company’s board of directors and management team. “With the successful launch of our Class A production base, the smooth progress of clinical trials, overseas business development, and CRDMO services, we are confident that C Ray Therapeutics will accelerate the development of innovative radiopharmaceuticals, technologies, and service platforms that maximize benefits for patients. Our goal is to become a leading innovative radiopharmaceutical enterprise not only in China but also globally.” googletag.cmd.push(function () { googletag.display('text-ad1'); }); Investment in radiopharmaceuticals has been on the rise over the past year, as big pharma have increased their activity in the space. Eli Lilly has been progressively increasing its reach into radiopharmaceuticals, with the acquisition of Point Biopharma for $1.4 billion last year, a $1.1 billion partnership with Aktis Oncology in May this year, and a recent acquisition deal with Radionetics Oncology potentially worth $1 billion in July. Other major players include Novartis, which acquired Mariana Oncology in May, and BMS, which entered the field at the end of last year with the $4.1 billion acquisition of RayzeBio. The growing interest in this area has also led to the creation of contract development and manufacturing organization (CDMO) facilities fully dedicated to radiopharmaceuticals .

并购放射疗法

2024-11-18

·医药魔方Pro

超7亿美元！诺华“加码”核药

11月18日，Ratio Therapeutics宣布与诺华子公司Novartis Pharma AG签订了全球独家许可和合作协议。Ratio致力于利用创新技术开发best-in-class放射性药物。此次合作主要聚焦下一代SSTR2靶向放射性药物。根据协议条款，Ratio将获得高达7.45亿美元的预付款和潜在里程碑付款，并有资格获得分级特许权使用费。Ratio将与诺华合作，推动临床前活动，以筛选靶向SSTR2的候选药物。诺华将负责所有剩余的开发、生产和商业化活动。 Ratio成立于2022年，总部位于波士顿。2024年1月，公司宣布完成5000万美元的B轮融，BMS也出现在投资者名单中。Ratio主打Trillium™和Macropa™两大技术平台。Trillium™用于调节候选分子的药代动力学（PK），提高药物可用性和肿瘤递送，同时降低副作用。Macropa™技术包含一种专有的螯合剂，其独特的化学性质使其易于制造，并提高了所得化合物的体内稳定性。Macropa™可与多种化合物一起使用，从小分子到多肽，甚至大多肽，如抗体。知识卡：靶向放射性药物（也被称为放射性配体疗法、RDC等）一般包含四部分：放射性同位素（radioisotope）、螯合剂（chelator，负责稳定或“笼化”放射性核素，以防止核素在到达目的地之前伤及无辜）、靶向配体（负责精准识别和结合肿瘤靶点）及连接子（linker，负责连接靶向配体和螯合剂）。 Ratio认为，结合Trillium™和Macropa™两大平台非常有可能开发出基于α粒子（actinium-225）的best-in-class放射性药物。目前公司在推进其首个FAP靶向放射性药物的开发，计划明年进入临床试验。而关于此次与诺华合作的靶点，医药魔方NextPharma®数据库显示，目前全球有20款左右SSTR2靶向放射性药物在研，进展最快的是BMS的RYZ101，处于III期临床。去年12月，BMS以41亿美元收购 RayzeBio获得了RYZ101等资产。诺华是核药赛道当之无愧的“王者”，目前手握Lutathera和Pluvicto两款明星产品，且有包括177Lu-FAP-2286、177Lu-NeoB、225Ac-PSMA-617在内的多款在研管线。2024年，诺华在核药赛道继续加码，5月以17.5亿美元收购了核药公司Mariana Oncology。参考资料： [1]https://ratiotx.com/2024/11/18/november-18th-2024-ratio-enters-license-and-collaboration-agreement-with-novartis-for-sstr2-targeting-radiotherapeutic-candidate/ [2]https://www.businesswire.com/news/home/20231225781528/en/%C2%A0Bristol-Myers-Squibb-Adds-Premier-Radiopharmaceutical-Platform-with-Acquisition-of-RayzeBio Copyright © 2024 PHARMCUBE. All Rights Reserved. 欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任

放射疗法临床3期引进/卖出并购临床结果

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药物(靶点)	适应症	全球最高研发状态

RYZ-101 ( SSTR2 )	功能性内分泌肿瘤更多	临床3期
RYZ-801 ( GPC3 )	GPC3阳性肝细胞癌更多	临床1期
RYZ-811 ( GPC3 )	GPC3阳性肝细胞癌更多	临床1期
卡铂 ( DNA )	广泛期小细胞肺癌更多	临床1期
Renal cell cancer therapy (RayzeBio) ( CAIX )	肾细胞癌更多	临床申请