PSMA-Positive Tumor

Vironexis’s off-the-shelf, single-dose gene therapies aim to deliver cancer treatments that are safer, more effective and long-lasting, and more easily manufactured and administeredLeveraging its TransJoin™ platform, Vironexis has built a pipeline of more than 10 product candidates for blood-based cancers, solid tumor metastasis prevention and a cancer vaccineVironexis’s foundational technology is based on pioneering, published research led by Timothy Cripe, M.D., Ph.D., at Nationwide Children’s HospitalVironexis’s $26 million seed financing was led by Drive Capital and Future Ventures, with participation from Moonshots Capital and Capital FactoryVironexis plans to advance its first two oncology programs into the clinic in Q4 2024 and 2025, respectively SAN DIEGO, Sept. 12, 2024 (GLOBE NEWSWIRE) -- Vironexis Biotherapeutics, focused on transforming the future of cancer treatment by pioneering AAV-delivered T-cell immunotherapy, launched from stealth today, unveiling its TransJoin™ AAV Gene Therapy Platform and a pipeline of more than ten product candidates for blood-based cancers, solid tumor metastasis prevention, and a cancer vaccine. Vironexis’s $26 million seed financing was led by Drive Capital and Future Ventures, with participation from Moonshots Capital and Capital Factory. The company has received clearance of its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) for VNX-101, its first gene therapy product candidate, for the treatment of CD19+ acute lymphoblastic leukemia. Vironexis anticipates initiating patient enrollment of a Phase 1/2 trial of VNX-101 in the fourth quarter of 2024, which will mark the first-ever clinical trial of an AAV-delivered cancer immunotherapy. VNX-101 has received both Fast Track Designation and Rare Pediatric Disease Designation from the FDA. “We’re excited to launch Vironexis from stealth and reveal our noteworthy progress advancing AAV-delivered T-cell immunotherapy,” said Samit Varma, co-founder and CEO of Vironexis. “Our novel technology builds on the power of T-cell immunotherapy while overcoming key shortcomings and challenges of existing approaches such as CAR-T and bispecific antibodies. We believe we have the opportunity to dramatically improve upon the safety, efficacy and durability of these drug classes, while streamlining manufacturing and significantly lessening the burden of treatment for patients. Our focus on execution has yielded an expansive pipeline and a clinic-ready lead program in just three years. We’re working as quickly as possible to transform the future of cancer treatments for patients.” TransJoin enables a patient’s body to express an engineered transgene that redirects T cells throughout the body to tumor cells. The proprietary technology requires only a single dose and provides a bridge that joins together T cells and tumor cells to promote long-term, continuous T cell-mediated tumor killing. The foundational technology for TransJoin was licensed from Nationwide Children’s Hospital. In 2022, research led by Timothy Cripe, M.D., Ph.D., Chief of the Division of Pediatric Hematology/Oncology/Bone and Marrow Transplant, describing the TransJoin technology was published in Science Advances [link here to paper]. Dr. Cripe is one of Vironexis’s co-founders, along with Mr. Varma, a seasoned biotechnology and gene therapy company entrepreneur, and Brian Kaspar, Ph.D., a notable gene therapy scientist-entrepreneur who founded AveXis, Inc. (acquired by Novartis) and pioneered the AAV gene therapy ZOLGENSMA®. “AAV is a proven delivery technology with multiple approvals since 2017. Recognizing the pivotal impact of AAV delivery for the treatment of rare diseases, we believed its unique ability to enable long-term, continuous expression of a therapeutic protein could be the missing link to overcome the myriad challenges associated with first-generation T-cell immunotherapies like CAR-T. We subsequently demonstrated the potential of this approach in the preclinical setting,” said Dr. Cripe. “It’s thrilling to now be on the cusp of seeing how this technology translates in the clinical setting. Our ultimate goal is to help a vastly broader population of patients realize the tremendous benefits of T-cell immunotherapy.” Vironexis is in the process of obtaining pre-IND input from the FDA for its second program, VNX-202, as a treatment for the prevention of metastatic HER2+ cancer (including breast cancer and other tumor types), and plans to start dosing patients in a Phase 1/2 clinical trial in 2025. The company’s other current product candidates include treatments for BCMA/GPRC5D+ multiple myeloma, CD19/20+ B-cell lymphoma; treatments to prevent metastases in GD2+ neuroblastoma, HER2+ gastric cancer, PSMA+ and MSLN+ pancreatic cancer, B7H3+ ostersarcoma and GP350+ nasopharyngeal cancer; a cancer vaccine for GP350+ nasopharyngeal cancer; and a treatment for CD19+ systemic lupus erythematosus, which Vironexis plans to partner for further development. Molly Bonakdarpour, Partner at Drive Capital commented, “As a portfolio investment, Vironexis offers an ideal blend of groundbreaking technology, impressive preclinical data, the potential for vast patient impact, and a founding team with deep, relevant expertise and a proven track record of company formation, strategic thinking, and successful execution. Vironexis’s notable productivity in a very short timeframe has been remarkable. We look forward to its upcoming transition to a clinical-stage company.” Steve Jurvetson, Co-Founder of Future Ventures, added, “We were drawn not only to the novelty of the TransJoin technology but also to its broad applicability, spanning treatments for blood-based cancers, solid tumor metastasis prevention, and cancer vaccines, as well as immune disorders. The versatility of this platform is truly standout, and the Vironexis team’s progress in rapidly building a pipeline that explores the expanse of these opportunities is extraordinary.” How TransJoin Works Vironexis’s TransJoin technology is designed to enable the expression of a secreted T cell engager that binds the tumor cell on one side (changeable depending on the product candidate indication target) and T cells via CD3 on the other side. CD3 is a protein that helps promote T-cell recognition of and activation against cancer cells. Following a single, one-time intravenous infusion, the TransJoin technology instructs the liver to continuously secrete the bispecific protein into the bloodstream to redirect T cells to tumor cells. TransJoin provides a bridge that joins T cells and tumor cells, resulting in long-term, consistent serum levels of the therapy and, thus, long-term, consistent T-cell-mediated tumor cell killing. TransJoin’s extremely low-dose AAV delivery minimizes toxicity and adverse events. About Vironexis Biotherapeutics Vironexis is focused on transforming the future of cancer treatment by pioneering AAV-delivered T-cell immunotherapy. Our TransJoin™ AAV Gene Therapy Platform enables the creation of off-the-shelf, single-dose gene therapies designed to overcome the key challenges and shortcomings of current immunotherapies, including CAR-T and bispecific antibodies. Our current pipeline includes more than ten product candidates for blood-based cancers, solid tumor metastasis prevention, and a cancer vaccine. Our lead program, VNX-101, for the treatment of CD19+ acute lymphoblastic leukemia, is anticipated to begin clinical trials in the fourth quarter of 2024. Visit us at vironexis.com and follow us on LinkedIn and X. Vironexis Media Contact:Liz MeloneMelone Communications, LLCliz@melonecomm.com

A new startup attempting to develop AAV gene therapies to treat cancer emerged from stealth Thursday morning with $26 million in seed funding — and a plan to quickly get into the clinic. Vironexis Biotherapeutics is aiming to get a Phase 1/2 trial up and running in October for what it describes as an “off-the-shelf” gene therapy, a term that has historically been connected to allogeneic CAR-T. Such therapies have proven difficult to develop, as they continue to face questions about their durability. And the FDA has not approved any. But rather than giving patients re-engineered white blood cells from donors, Vironexis’ gene therapy is designed to deliver an engineered gene. The gene prompts the body to continuously create a protein that links tumor-fighting T cells on one side and tumor cells on the other. CEO Samit Varma likened the process to an immunotherapy that the body produces itself. What Vironexis means by “off-the-shelf” is that there is no individualized manufacturing process for its therapy like for autologous CAR-T, where a patient’s own white blood cells are removed, genetically modified and then readministered, Varma told Endpoints News . Instead, its process allows the therapy to be made in bulk and stored in freezers at treatment sites. “The human immune system is the most powerful drug in the world, and so we’re leveraging that power by introducing this gene that can then identify these tumor cells,” Varma said. Timothy Cripe, a co-founder whose research at Nationwide Children’s Hospital helped launch the company, also said he believes the approach is safer than traditional CAR-T. With the program, called VNX-101, the immune-fighting reaction ramps up more slowly as the protein continues to be expressed and accumulates over time. The first kind of cancer Vironexis wants to attack is CD19-positive acute lymphoblastic leukemia, a setting where two autologous CAR-Ts are currently approved: Novartis’ Kymriah and Gilead and Kite’s Tecartus. Varma said the FDA granted the program IND clearance and that the company already has manufactured enough of VNX-101 to begin the trial next month. Vironexis also plans to expand to other areas at a steady march, and it expects another program called VNX-202 to start a basket trial for HER2-positive cancers in 2025. Design-wise, VNX-202 contains the same AAV delivery vehicle as VNX-101, but researchers replaced the gene responsible for the anti-CD19 proteins with a gene for HER2. Varma said its approach can allow the company to go into many different cancer settings with few modifications. So far, Vironexis has conducted preclinical testing for BCMA-, PSMA- and GD2-positive cancers, among several others. They’re also “actively” in discussions for a Series A, he said, and hopes to raise one “within the next several months.” Also co-founding Vironexis is Brian Kaspar, the former AveXis founder and CSO who helped develop the SMA gene therapy Zolgensma and was let go after it was acquired by Novartis following a data manipulation scandal in 2019. Kaspar has denied any wrongdoing. In an interview Wednesday, Kaspar said he hopes Vironexis can follow the commercialization path AveXis and Novartis laid out with Zolgensma, which he added other gene therapy companies have struggled with. Varma also noted that he’s worked with Kaspar at multiple companies since AveXis and that the due diligence always comes back clean. “This is actually our fourth company, post-AveXis departure, that Brian and I have done together, and in each one of those, it’s been a massive amount of diligence,” Varma said. “It’s been investigated by probably 12 different top law firms in the country, every time we did an acquisition or anytime we raised money.” Drive Capital and Future Ventures led the seed round, with Moonshots Capital and Capital Factory also participating.

本次大会的主题为“砥砺深耕·笃行致远”，热情邀请全国相关领域专家、学者、科研骨干、企业代表与会交流。 放射性药物正在成为大制药公司和投资者的新宠。 放射性药物的独特之处在于利用靶向配体，将放射线直接送达肿瘤细胞，通过破坏肿瘤细胞的DNA来消灭它们。这种方法展示了诸多优势，不仅可以减少药物耐药性，还提供了与免疫治疗结合的机会。更神奇的是，放射性药物的成像功能可以在治疗前或治疗过程中可视化肿瘤位置和治疗吸收情况，从而提升患者选择和剂量准确性。这种“诊疗结合”的方法提供了其他疗法难以比拟的信息。 放射性药物的魅力不仅限于此。它们还扩大了药物靶标的范围，即使是那些低表达靶标的肿瘤也能被有效摧毁。 诺华的Lutathera和Pluvicto等药物的成功，激发了一波又一波的收购浪潮。大制药公司纷纷通过收购拥有临床资产和制造能力的公司来涉足这一领域，推动了数十亿美元的交易。 然而，这片充满希望的领域也面临着不小的挑战。放射性药物的制造和分发涉及复杂的物流问题。同位素供应的不稳定性、核医学专家和治疗设施的短缺，都限制了其推广。 尽管技术尚未完全成熟，但这个领域正在快速发展，未来有望带来更多突破。 1 β辐射之外：放射性药物的前沿突破 诺华在放射性药物领域扮演着先锋的角色。诺华的Lutathera和Pluvicto分别于2018年和2022年获批，这两种药物利用同位素Lu-177提供β辐射。这种中等强度的电子流能够穿透2-10毫米（相当于几十个细胞的厚度），并有效切割DNA链。在Lutathera中，β辐射专门靶向神经内分泌肿瘤（NET）表面的生长抑素2型受体（SSTR2），其配体是生长抑素类似物oxodotreotide。而Pluvicto则通过抑制前列腺特异性膜抗原（PSMA）的肽vipivotide，精准打击前列腺癌细胞。 在3期临床试验中，这两种药物都显著提高了晚期疾病患者的整体生存率。最近，在NETTER-2试验中，Lutathera与生长抑素类似物奥曲肽联合使用，将新诊断GEP-NET患者的死亡或进展风险降低了72%。而Pluvicto在没有经过化疗的PSMA阳性转移性去势抵抗性前列腺癌患者中依然表现出色，放射性无进展生存期达到翻倍。诺华预计将在2024年申请Pluvicto在早期疾病中的额外批准。 诺华并不孤单。其他制药公司已纷纷加入这一行列，据数据和分析公司GlobalData的数据，在最近的五年间，放射性药物的风险投资额增长了五倍之多。 放眼未来，许多下一代放射性药物正在利用α辐射进行治疗。α辐射强大的短距离氦核能够穿透辐射范围内的DNA链，造成大部分不可修复的损伤，不留任何抵抗的余地。由于它们只能穿透一两个细胞的直径，可能不会伤害到附近的健康细胞。而且对于对β射线产生耐药的患者，α射线可能是更有效的选择。 目前，许多α辐射药物正在开发中。例如，RayzeBio（现为BMS）的RYZ101将Act-225传递到SSTR2受体，正在针对不再对Lutathera反应的GEP-NET进行3期临床试验。Fusion（现为阿斯利康）的主要候选药物使用Act-225靶向PSMA阳性肿瘤。Act-225也出现在拜耳、Convergent Therapeutics和Actinium Pharmaceuticals的临床项目中。诺华通过收购Mariana Oncology，获得了一个处于临床前阶段的小细胞肺癌Act-225候选药物。 α辐射不仅能够有效杀死癌细胞，还能通过利用免疫系统，产生新抗原，使肿瘤对免疫治疗敏感。α辐射的短距离、高能量打击使其成为更有效的癌细胞杀手，比低能量的β辐射更具优势。 在便利性方面，α射线也有显著优势。接受Lutathera或Pluvicto治疗的患者在治疗后一周内必须远离孕妇和儿童，而α射线则减少了隔离要求，这对于患者和家庭来说是一个“大加分项”。 尽管对α射线充满热情，但目前的人类临床数据依然较少。强生的基于Act-225的前列腺癌候选药物在1期剂量发现试验中，57名接受药物治疗的患者中有4名因治疗相关不良事件死亡，但在高度预处理患者中表现出“深刻且持久的”反应。 关于α射线的长期安全性，仍需进一步研究。 2 Act-225与Pb-212的α同位素之争 在α放射性同位素的世界里，Act-225和铅Pb-212正展开一场激烈的角逐，两个对手各有各的独门秘籍，也各有各的麻烦。Act-225有个让人又爱又恨的特点，那就是它复杂的衰变链。这种同位素会衰变成多个会发射α射线的“子同位素”，这增加了它的治疗潜力。然而，如果这些子同位素一不小心跑出了肿瘤的控制范围，就可能带来安全隐患。2023年，RayzeBio在研究中发现，大部分α辐射仍停留在肿瘤内，但这只是初步数据，离全面了解还有一段路要走。Act-225的另一个挑战是，它和子同位素在某些点释放伽马射线，这让准确测量它的活动变得相当棘手。 相比之下，铅Pb-212的衰变链就显得干净利落，只发射一个α粒子，因此辐射偏离的风险较小。Pb-212还有一个绝妙的搭档——伽马发射同位素Pb-203，这对黄金组合能确保治疗和成像的生物分布一致。然而，Pb-212的11小时半衰期让物流和运输成了头疼的问题，而Act-225的半衰期超过10天，对废物管理提出了更大的挑战。 供应链的动态也为Act-225和Pb-212的竞争添了一把火。几年前，Pb-212比Act-225更难获取，这也解释了为什么基于Act-225的候选药物进展更快。生产Act-225需要专业设备和独立供应链，导致了瓶颈。RayzeBio的3期RYZ101试验就因Act-225短缺而推迟。制药公司和开发商们纷纷签署供应协议，甚至收购供应商，以确保手里有足够的货源。2024年4月，Telix Pharmaceuticals收购了ARTMS及其基于回旋加速器的同位素生产平台。同时，Orano Med、Perspective和Artbio也在大力开发内部Pb-212生成方法。2024年初，Orano Med在法国建设了基于Pb-212的放射性配体生产设施，计划成为欧洲首个工业规模的生产基地。 在这个竞争激烈的领域，FDA对“α优先”治疗方法持开放态度，特别是在罕见的GEP-NET适应症中。2024年2月，RadioMedix和Orano Med的基于Pb-212的GEP-NET候选药物AlphaMedix成为首个获得FDA突破性治疗认定的靶向α发射疗法，目前处于2期阶段。FDA还授予Perspective Therapeutics的基于Pb-212的1/2期神经内分泌肿瘤候选药物快速通道地位，适用于一线治疗。 在这个不断变化和充满希望的领域里，Act-225和Pb-212都在奋力争夺未来的医疗市场，带来更有效、更安全的癌症治疗选择。 3 配体设计的演变 随着同位素的优缺点逐渐显现，配体设计也在不断进化，变得更加精细和多样化。双配体与同位素的基本原则是将同位素的半衰期与靶向剂的动力学相匹配。衰变较慢的同位素适合停留时间较长的配体，如抗体，而衰变较快的小分子或肽则更适合那些衰变较快的同位素。 配体与靶标的相互作用也影响同位素的选择。例如，Convergent的2期前列腺癌候选药物将全尺寸抗体rosopatamab与衰变较慢的Act-225连接。这是因为靶标PSMA受体会内化抗体及其连接的同位素，Act-225的多步衰变链可能更容易保持在控制范围内。而Telix的3期前列腺癌放射性药物使用相同的抗体，但连接的是衰变较慢的Lu-177。 全尺寸抗体在特异性方面无可比拟，但其尺寸和持久性可能成为一个缺点，因为放射性同位素不应停留太久。较小的肽则提供了一个理想的中间地带，结合了抗体的特异性和靶向亲和力，同时具备更大的肿瘤细胞穿透性和更快的清除率。 肽可以根据任务需求进行设计。现在，制药公司们正在定制肽，以达到最佳的靶向亲和力、肿瘤穿透、载荷容量和清除的组合。减少肾脏中的积累尤为重要，因为肾脏会重吸收氨基酸，导致放射性同位素的积累。一些公司如3B已经找到方法使肽在肾脏中“屏蔽”，使其通过尿液排出，这项技术已被多家制药公司采用。 小分子在放射性治疗复兴中也占有一席之地。一些研究正在开发针对GPCR的小分子-同位素组合。 随着这场不断变化的战斗愈演愈烈，研究人员正如同精细调制乐器般，调整配体与同位素的搭配，使每一组合都能奏出最动人的乐章。无论是尺寸庞大的抗体，还是灵活敏捷的肽和小分子，它们都在这一波放射性治疗的革命中，发挥着至关重要的作用。 4 放射性药物的靶点正多样化 随着同位素和定制配体的多样化，放射性药物的靶标范围迅速扩展，远远超出了传统的SSTR2和PSMA。不同的靶标类型和位置需要匹配特定类型的辐射。例如，碳酸酐酶IX（FAP）在多种癌症中表达，位于癌细胞周围的组织，而非癌细胞本身。杀死这些癌细胞需要长程β辐射，如Lu-177。诺华的FAP靶向Lu-177目前正处于1/2期临床试验阶段，这是他们在2022年从Clovis Oncology手中收购的项目。 针对侵袭性脑癌如复发性胶质母细胞瘤，研究人员正在开发以多聚腺苷二磷酸核糖聚合酶（PARP）酶为靶点的放射性药物。Ariceum正在将PARP抑制剂与放射性I-123结合，后者发射超短程的Auger辐射并发出有助于成像的伽马射线。由于PARP位于细胞DNA的顶部，短程辐射能理想地减少对邻近神经元的影响。Auger辐射虽然关注较少，但其低能电子流可能对顽固的癌细胞进行有针对性的“最后一击”，清除癌症残余细胞。 最近，放射性药物研发管道中出现了众多创新靶点，展示了这一领域的多样性和前景。例如，Telix的2期晚期肾癌项目结合了Lu-177和girentuximab，靶向碳酸酐酶IX（CAIX）；诺华的1期Lu-177-NeoB项目和Orano Med的1期Pb-212候选药物都靶向促胃泌素释放肽受体（GRPR）；强生公司的Act-225基础的1期前列腺癌项目瞄准了人激肽释放酶2（kallikrein 2）；Abdera Therapeutics的研究集中在DLL3，用于治疗小细胞肺癌（SCLC）和大细胞神经内分泌癌（LCNEC）。 这仅仅是个开始。放射性辐射的强大威力仅需少量分子即可消灭癌细胞，打开了潜在靶标的大门，包括那些低表达的靶标。 5 高门槛 尽管下一代放射性药物即将获得批准，它们仍面临独特的物流挑战。同位素供应、产品组装、规模化制造，以及在同位素衰变时间范围内递送给患者，都需要极高的专业知识、设施和协调。诺华拥有四个放射性药物制造站点，其中包括2024年1月获得FDA批准的第二个美国站点，每年可生产25万剂Pluvicto。即便如此，这个资源丰富的制药巨头也遇到了种种困难。许多较小的开发商希望诺华铺设好高速公路，然后他们能在其上行驶。 诺华目前只销售两种使用相同放射性同位素的产品。其他产品将需要不同的分销和治疗基础设施。比如，使用短寿命的Pb-212的产品必须靠近治疗中心生产，且需要大量的屏蔽来防护强烈的伽马射线。基于Act-225的产品废物需按指导方针存储100天，这至少需要10个半衰期的安全同位素存储器。患者可能需要在医院停留更长时间。 另一个复杂因素是放射性药物必须由经过培训的核医学医生管理。尽管Lutathera和Pluvicto的成功吸引了更多人员加入，但肿瘤学家和核医学专家之间的协调需求，特别是在不同地点或与不同医疗提供者合作时，仍然是个挑战。 一些公司正在开发可能有助于解决这些问题的方法。Y-mAbs便是一家这样的公司。他们的预靶向放射免疫治疗双特异性自我装配和分解SADA平台，从MSKCC和MIT获得了许可。 SADA平台的独特之处在于其两步给药法，将SADA的预靶向和放射性核素的递送分开。第一阶段首先由肿瘤学医生进行非放射性的SADA给药，这意味着医生可以更直接地参与治疗。未结合的抗体片段会迅速被身体排出，而结合了肿瘤靶抗原的四聚体则会停留在肿瘤细胞表面。接着，在第二阶段，患者会接受一种放射性有效载荷，特异性地针对与肿瘤靶抗原结合的SADA分子。第二步需要授权用户操作，但预计比传统放射性药物输注更快。 这种方法不仅能够精准靶向肿瘤，还能最大限度地减少对正常组织的辐射。 — 小结 — 放射性药物领域正在迎来前所未有的繁荣期。根据Evaluate的预测，到2028年，这些疗法的年销售额预计将超过60亿美元。如果包括广泛使用的诊断剂如99mTc，这一数字将翻倍。正因如此，投资者不断涌入这个充满希望和潜力的领域。 Evaluate预测的全球核药市场 尽管放射性药物行业依然年轻，但其发展空间广阔。通过今后多方面的努力，放射性药物有望成为肿瘤治疗中的重要一环，推动癌症治疗进入一个新的时代。 参考文献： 1.Precision radiation opens a new window on cancer therapy 2.The radiopharmaceutical renaissance: radiating hope in cancer therapy. 同写意媒体矩阵，欢迎关注↓↓↓