Artios Pharma Ltd.

Artios Pharma, a startup developing drugs that weaken a tumor’s ability to maintain its DNA, announced positive results in a subset of patients with advanced cancer. It’s the first big data reveal for the Cambridge, UK-based startup, which has been relatively quiet since 2021, when it struck a drug discovery partnership with Novartis and raised $153 million in Series C financing. The company’s drug, called ART0380, inhibits a DNA repair enzyme called ATR. When administered with a low dose of the chemotherapy irinotecan, the drug shrank tumors in 37% of patients whose cancer was considered “deficient” in another DNA damage response protein dubbed ATM, according to data from a Phase 1/2 study. In patients whose tumors lacked the ATM protein entirely, the response rate was 50%, with a median duration of response of 5.7 months so far. The response rate was 22% in patients with low levels of ATM. Patients with the ATM protein, however, did not respond to the therapy. “All those patients unfortunately progress quickly and unfortunately die very quickly,” Artios Chief Medical Officer Ian Smith told Endpoints News in an interview. The new data, presented Tuesday at the American Association for Cancer Research meeting, comes from 58 patients with advanced-stage and metastatic solid tumors who were treated at the dose the company plans to use in a Phase 2 study. Artios CEO Niall Martin told Endpoints that the company has funds “through 2026.” He said the startup is looking to raise another round of private funding to test its ATR inhibitor in pancreatic and colorectal cancers before pursuing bigger and broader tissue-agnostic studies. Martin said the company’s partnership with Novartis, which wasn’t focused on its ATR inhibitor, identified several targets that could potentially be paired with Novartis’ radioligand therapies, including its prostate cancer drug Pluvicto, and discussions are underway on next steps. Artios had struck a partnership with Merck KGaA in 2020 to search for drugs that target other DNA repair proteins, but Martin told Endpoints that partnership has ended. Artios was founded in 2016 to discover a new wave of drugs that target complex networks of proteins dedicated to the faithful replication and preservation of our genomes. While cancer can survive, and even thrive, with some DNA repair enzymes missing, too many missing pieces can cause the cancer to self-destruct. A class of drugs called PARP inhibitors exploit this vulnerability by blocking the eponymous DNA repair protein in tumors that have mutations in genes called BRCA1 and BRCA2, which are also important for DNA repair. Several companies have been searching for the next combination of targets that can deliver a similar double whammy to tumors, but progress has been slow. “The field hasn’t really evolved much since PARP inhibitors,” Martin said. “So we’ve been really thinking about what are the layers of DNA damage that are created in tumors that could be used as their sort of Achilles heel.” One of those layers, according to Artios, is a phenomenon called replication stress, which can occur when DNA replication, a key step for dividing cells, is blocked. ATR and ATM are two proteins that detect and clear up these blockages. Many forms of chemotherapy obstruct DNA replication. By first inducing a bit more of that stress with a low dose of chemo — but not enough to kill the cancer itself — and then blocking ATR in tumors with little to no ATM, Artios hoped to deliver a triple whammy to tumors. “There’s always been a push to get rid of chemotherapy and have targeted drugs,” Smith said.“But if you can’t get rid of chemotherapy, what you can do is really minimize it. And that’s what we’ve done here.” Smith said the company saw two complete responses, including one in a 62-year-old female who had pancreatic cancer but has been off treatment and cancer-free since August 2023. Neutropenia, a decline in white blood cells, was the most common side effect seen in 53% of patients, with grade 3 neutropenia in 45% of patients. Anemia occurred in 41% of patients. Fatigue, diarrhea, nausea and vomiting were also common side effects. Several other drugmakers have developed their own ATR inhibitors, but lackluster results have caused some pharma companies, including Bayer and Roche, to discontinue or pare back these efforts. “ATR inhibitors have been languishing,” Smith said. “The response rates are low relative to the toxicity that you tend to get.” Roche cut its partnership with Repare Therapeutics in 2024, which paused its ATR inhibitor program earlier this year after modest responses in only 19% and 17% of endometrial and ovarian cancer patients, respectively. Merck KGaA dropped its first ATR inhibitor, berzosertib, but is still testing a second one, called tuvusertib. And AstraZeneca is testing its ATR inhibitor ceralasertib in a Phase 3 study in lung cancer with its immunotherapy Imfinzi, which is expected to complete in August. Artios executives told Endpoints that other ATR inhibitors have faltered for three reasons: the drug’s half-life was too long, leading to intolerable toxicity; the drug was tested as a monotherapy, leading to low efficacy; or the drug was paired with the wrong therapies or tested in the wrong genetic subtypes of cancer. Martin said the company plans to develop a companion diagnostic to identify patients that are most likely to respond to its drug, with an initial focus on ATM. But Artios is looking for other biomarkers that may make tumors vulnerable to ATM inhibitors too. “This whole process of replication stress can be in up to 30% to 40% of tumors,” Martin said. “So there’s a huge area of biology which no one really has tapped into.”

Boehringer Ingelheim is paying an upfront fee, of publicly undisclosed size, for global rights to the ALT program.\n Boehringer Ingelheim has slipped another piece of its oncology R&D strategy into place, partnering with Tessellate Bio on a synthetic lethal program in a deal worth more than 500 million euros ($570 million) in biobucks. European biotech Tessellate exited stealth in 2023 with a focus on novel synthetic lethality approaches. PARP inhibitors have shown the potential to shrink tumors by targeting pairs of genes that are essential for the survival of cancer cells. Companies including AstraZeneca and Merck KGaA are studying forms of synthetic lethality beyond the homologous recombination deficiency pathway targeted by PARP drugs. Tessellate has found a largely unclaimed piece of territory, namely tumors that depend on alternative lengthening of telomeres (ALT) for their growth. About 10% to 15% of cancers rely on ALT, according to the biotech. ALT-positive tumors are associated with poor prognosis and a lack of targeted therapies. Boehringer is paying an upfront fee, of publicly undisclosed size, for global rights to the ALT program. Once milestones and other fees are factored in, the value of the agreement could swell to more than 500 million euros.  Telomeres, the caps at the ends of chromosomes, shorten with each cell division and limit the life span of cells. Some cancers, including many sarcomas, gliomas and neuroepithelial tumors, use ALT to maintain telomere length. Tumors’ reliance on ALT creates opportunities to selectively kill cancer cells by targeting the mechanism. Tessellate said it has developed inhibitors of an undisclosed target that helps enable uncontrolled growth of ALT-positive cancer cells. Blocking the target drives DNA damage, replication stress and cell death, the biotech said. When it exited stealth, Tessellate said its lead ALT program targeted the FANCM protein complex. Studies have shown FANCM suppresses DNA replication stress at ALT telomeres. Artios Pharma, another European biotech, has a discovery-stage ALT program, but the industry’s efforts to expand synthetic lethality have largely focused on other pathways to date. AstraZeneca, which helped put PARP inhibitors on the map, is running trials of drug candidates that hit targets including ATR. Other targets include WEE1, USP1 and POLθ.    

核药领域正在进入收获期。全球核药龙头捷报频传——诺华的两款核药2024年销售收入首次突破20亿美元；远大医药（0512.HK）交出的2024年答卷同样让人眼前一亮，公司实现收入约116.45亿港元，其中核药板块的收入增长抢眼，共实现收入5.9亿港元，同比增长近177%。▍核药，精准的魔法炸弹近年来，放射性偶联药物已成为癌症治疗的一种有前途的方式。这类药物将放射性同位素与包括抗体、多肽或小分子药物进行偶联，从而将放射性同位素精确靶向递送到癌细胞。与传统放疗相比，这种方法具有许多潜在优势，包括最大限度地减少对健康细胞的损害，并能够到达外部射线辐射无法到达的深部肿瘤。区别于普通药物，核药中放射性核素发出的粒子或射线是医学诊断和治疗的应用基础，由于核素本身半衰期很短，再加上核素会对生产人员、患者、医护人员等造成的辐射损伤，核药从生产到使用，受到政策严格监管。▍率先布局者，已尝到甜头随着核药市场热度升温，提前布局的企业已尝到一些甜头。远大医药2024年财报显示，公司2024年实现收入116.4亿港元。其中核药板块的收入增长抢眼，共实现收入5.9亿港元，同比增长近177%。钇[90Y]微球注射液是远大医药主要的核药肿瘤药，从海外引进，于2022年2月在中国获批，当年5月正式在中国投入应用。这款核药的销售放量，正在助推远大医药核药板块收入增长。目前公司还有3款创新RDC产品以及1款介入治疗产品处于III期临床阶段，其中，用于诊断前列腺癌TLX591-CDx预计可于2025年完成三期临床研究。2024年诺华两款核药，Pluvicto与Lutathera收入达到21.16亿美元。自2022年3月于美国获批上市以来，Pluvicto增长势头强劲，上市首年，Pluvicto销售额为2.71亿美元；2023年，销售额飙升至9.8亿美元，2024实现销售13.92亿美元（同比增长42%），首次进入“10亿美元分子俱乐部”。目前针对Pluvicto仍有四个适应症在研，其中针对转移性激素敏感前列腺癌（mHSPC）的研究处于Ⅲ期临床阶段，预计于2025年完成并计划提交申请。Lutathera得益于适应症范围的扩大（纳入了12岁及以上SSTR+胃肠胰神经内分泌肿瘤儿童患者），实现7.24亿美元（同比增长20%），在2-3年内也将进入10亿美元分子行列。▍核药领域，重磅交易不断基于两款核药Pluvicto和Lutathera的潜力，近年来MNC和国际资本大力布局核药资产以“占位”下一个重磅炸弹，仅2024年MNC便完成了3笔核药并购交易。2024年5月，诺华以10亿美元预付款+7.5亿美元里程碑收购Mariana Oncology，以扩大其放射性药物管道并增强研发能力。该协议包括临床前RLT候选人，重点是小细胞肺癌治疗MC-339。诺华通过收购（包括高级加速器应用和Endocyte）在该领域不断增长，最近与Artios Pharma、iTheranostics和PeptiDream签署了许可协议，以开发目标RLT。2024年3月19日，国际制药巨头阿斯利康（AstraZeneca）宣布以20亿美元的价格收购Fusion Pharmaceuticals，其将成为阿斯利康的全资子公司。Fusion公司当时最领先的研发项目是前列腺特异性膜抗原（PSMA）靶向的放射性疗法——FPI-2265，该疗法作为转移性去势抵抗的前列腺癌（mCRPC）的治疗方法，正在进行2期临床试验。2023年12月16日，百时美施贵宝（BMS）宣布以41亿美元的价格收购核药生物技术公司RayzeBio。该交易为BMS带来RayzeBio基于α核素的差异化放射性药物平台及多款在研创新产品药物开发项目，包括RYZ101、RYZ801等创新靶向核药，极大丰富了其肿瘤产品管线。当下，核药开发领域竞争激烈，更多适应症、更多靶点的创新药物开发，成为各司角逐的高地。 本文编辑：张杰参考资料已尝到核药销售甜头的远大医药，今年想要推动自研核药出海核药一哥发威！收入井喷领跑千亿蓝海市场20亿美元！阿斯利康收购核药公司Fusion，加速下一代癌症治疗核药的开发溢价100%!BMS以41亿美元收购RayzeBio 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号   粉丝群/投稿/授权/广告等请联系公众号助手 觉得本文好看，请点这里↓