Ixabepilone

Phase 2 study evaluating the utility of a DRP®companion diagnostic for cisplatin supports its abilityto predict drug response in certain breast cancer patients Boston, MA (May 30, 2023) — Allarity Therapeutics, Inc. (“Allarity” or the “Company”), a clinical-stage pharmaceutical company developing novel oncology therapeutics together with drug-specific DRP® companion diagnostics for personalized cancer care, today announced the results of a prospective Phase 2 clinical study of the Company’s proprietary DRP® technology that will be presented in a poster at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting on June 3, 2023. In the Phase 1/2 study, researchers analyzed the transcriptomic profiles of 37 evaluable metastatic breast cancer (mBC) patients and, based on analysis of biomarkers comprised within a DRP® signature, assigned response likelihood scores (DRP® 0-100) of patient tumors to a targeted, liposomal form of cisplatin (LiPlaCis™). Data from the poster presentation will show that the cisplatin-DRP® identified all four mBC patients who demonstrated a partial response (PR) in the trial as likely responders to the LiPlaCis™ treatment regimen using a DRP80+ score as a cut-off for likely responders. In addition, the cisplatin-DRP® also identified mBC patients demonstrating other efficacy signals, including improved progression-free survival. Based on these data, researchers concluded that the cisplatin-DRP® companion diagnostic can differentiate, in a statistically significant way, clinical responders and non-responders to cisplatin administered as LiPlaCis™. “While our proprietary DRP® companion diagnostics have been extensively validated in numerous retrospective analyses across multiple forms of cancer and many drug types, these data represent the first prospective clinical study showing that our technology can predict actual patient responses ahead of potential treatment,” said James G. Cullem, Chief Executive Officer of Allarity Therapeutics. “The ability to differentiate likely responders to a specific drug regimen prior to treatment has the potential to provide improved patient benefits and potential clinical trial efficiencies, and we are excited that these data will be shared with our colleagues at this year’s ASCO meeting.” Using a proprietary systems biology algorithm, Allarity’s DRP® technology analyzes transcriptomic differences between cell lines that are sensitive and resistant to provide a biomarker signature of drug response and resistance. The DRP® platform further refines the predictive signature through a clinical relevance filter (created from more than 3,000 actual tumor biopsy samples from a broad range of cancer drug clinical trials) to eliminate unnecessary biomarkers. By remaining agnostic to what influences tumor response or resistance to a drug, DRP® enables the identification of unknown biomarkers crucial to drug response or resistance. Allarity conducted the study in collaboration with investigators at hospitals in Denmark and its CRO Smerud Medical Research International AS. The LiPlaCis™ program is currently licensed to CHOSA Oncology AB for further clinical development. The poster presentation details are as follows: Poster Title: “Predictive biomarker for cisplatin in prospective phase 2 of liposomal cisplatin in metastatic breast cancer.” Authors: Nielsen, D., Jakobsen, E,H., Langkjer, S.T., Danoe, H., Balslev, E., Knoop, A., … Lassen, U.N. Abstract Number: 3130 Session Title: Developmental Therapeutics—Molecularly Targeted Agents and Tumor Biology Date and Time: 6/3/2023, 8:00 AM-11:00 AM local time About Allarity Therapeutics Allarity Therapeutics, Inc. (Nasdaq: ALLR) develops drugs for personalized treatment of cancer guided by its proprietary and highly validated companion diagnostic technology, the DRP® platform. The Company has a mature portfolio of three drug candidates: stenoparib, a PARP inhibitor in Phase 2 development for ovarian cancer, and in Phase 1 development for advanced solid tumors in a combination treatment with dovitinib, a pan-tyrosine kinase inhibitor (pan-TKI) that has previously been developed through Phase 3 in renal cancer; and IXEMPRA® (Ixabepilone), a microtubule inhibitor approved in the U.S. and marketed by R-PHARM U.S. for the treatment of second-line metastatic breast cancer, currently in Phase 2 development in Europe for the same indication. Additionally, the Company has rights in two secondary assets: 2X-111, a liposomal formulation of doxorubicin for metastatic breast cancer and/or glioblastoma multiforme (GBM), which is the subject of discussions for a restructured out-license to Smerud Medical Research International AS; and LiPlaCis®, a liposomal formulation of cisplatin and its accompanying DRP®, being developed via a partnership with CHOSA Oncology AB for late-stage metastatic breast cancer. The Company is headquartered in the United States and maintains an R&D facility in Hoersholm, Denmark. For more information, please visit the Company’s website at . About the Drug Response Predictor – DRP® Companion Diagnostic Allarity uses its drug-specific DRP® to select those patients who, by the genetic signature of their cancer, are found to have a high likelihood of responding to the specific drug. By screening patients before treatment, and only treating those patients with a sufficiently high DRP® score, the therapeutic response rate can be significantly increased. The DRP® method builds on the comparison of sensitive vs. resistant human cancer cell lines, including transcriptomic information from cell lines combined with clinical tumor biology filters and prior clinical trial outcomes. DRP® is based on messenger RNA from patient biopsies. The DRP® platform has proven its ability to provide a statistically significant prediction of the clinical outcome from drug treatment in cancer patients in 37 out of 47 clinical studies that were examined (both retrospective and prospective), including ongoing, prospective Phase 2 trials of Stenoparib and IXEMPRA®. The DRP® platform, which can be used in all cancer types and is patented for more than 70 anti-cancer drugs, has been extensively published in peer-reviewed literature. Follow Allarity on Social Media LinkedIn: Twitter: Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements provide Allarity’s current expectations or forecasts of future events. The words “anticipates,” “believe,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “might,” “plan,” “possible,” “potential,” “predicts,” “project,” “should,” “would” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. These forward-looking statements include, but are not limited to, statements related to the expected availability of capital to fund its anticipated clinical trials, statements related to advancing dovitinib in combination with stenoparib or another therapeutic candidate or other approved drug, any statements related to ongoing clinical trials for stenoparib as a monotherapy or in combination with another therapeutic candidate for the treatment of advanced ovarian cancer, or ongoing clinical trials (in Europe) for IXEMPRA® for the treatment of metastatic breast cancer, statements relating to the effectiveness of the Company’s DRP® companion diagnostics platform in predicting whether a particular patient is likely to respond to a specific drug, and statements related to the Company’s ability to regain compliance with the Nasdaq Listing Rule. Any forward-looking statements in this press release are based on management’s current expectations of future events and are subject to multiple risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that the Company is not able to raise sufficient capital to support its current and anticipated clinical trials, the risk that results of a clinical study do not necessarily predict final results and that one or more of the clinical outcomes may materially change following more comprehensive reviews of the data, and as more patient data become available, the risk that results of a clinical study are subject to interpretation and additional analyses may be needed and/or may contradict such results, the receipt of regulatory approval for dovitinib or any of our other therapeutic candidates or, if approved, the successful commercialization of such products, the risk of cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies will not be repeated or observed in ongoing or future studies involving our therapeutic candidates, and the risk that the current COVID-19 pandemic will impact the Company’s current and future clinical trials and the timing of the Company’s preclinical studies and other operations. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled “Risk Factors” in our Form 10-K annual report on the Securities and Exchange Commission, available at the Securities and Exchange Commission’s website at , and as well as discussions of potential risks, uncertainties and other important factors in the Company’s subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and the Company undertakes no duty to update this information unless required by law. ### U.S. Media Contact: Mike Beyer Sam Brown, Inc. +1 (312) 961-2502 mikebeyer@sambrown.com EU Media Contact: Thomas Pedersen Carrotize PR & Communications +45 6062 9390 tsp@carrotize.com Attachment Allarity - Press Release ASCO presentation

本文参考2022年发表在Journal of Hematology & Oncology的一篇药物综述文章《Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021》，介绍1991-2021年FDA批准的24种乳腺癌治疗新药（这是该文作者统计的，不一定涵盖全）。背景乳腺癌在女性中很常见（男性约占乳腺癌患者的1%）。仅乳腺癌就占女性癌症病例的24.5%和癌症相关死亡的15.5%，并在2020年超过肺癌成为最常诊断的癌症之一 。1991-2021年，FDA 批准了24种乳腺癌治疗药物（包括18种小分子、三种单抗和三种ADC，这是该文作者统计的，不一定涵盖全），比任何其他类型的实体瘤都多。1）激素受体 (HR) 阳性乳腺癌，包括雌激素受体 (ER) 和/或孕激素受体 (PR) 阳性乳腺癌，占所有乳腺癌病例的70%以上，并导致约50%的乳腺癌死亡。2）HER2阳性乳腺癌占所有乳腺癌病例的13~15%，并且与侵袭性和转移行为相关 。3）在超过5%的乳腺癌病例中观察到BRCA1/2突变。BRCA1/2突变通常表明通过同源重组修复DNA DSB的缺陷 ，并使患者易患乳腺癌、卵巢癌和其他癌症。4）三阴性乳腺癌（TNBC）被定义为缺乏ER、PR和HER2表达的乳腺癌，占所有乳腺癌病例的10~15%，是乳腺癌中预后最差的亚型。下面分a-m分别介绍具体的药物。a）1991-2021年FDA批准上市的乳腺癌治疗药物情况b）微管抑制剂在细胞毒性药物中，多西紫杉醇（docetaxel）可能是最著名的微管抑制剂之一。多西紫杉醇与其类似物紫杉醇共享相同的β-微管蛋白紫杉烷结合位点，但显示出更有效的抗肿瘤活性。它通过与游离β-微管蛋白结合并诱导微管聚合来发挥其活性，从而导致细胞周期停滞和死亡。伊沙匹隆（ixabepilone）是埃博霉素B的β-内酰胺类似物，以与紫杉醇类似但不完全相同的方式结合微管蛋白，并在含有P-糖蛋白表达或突变微管蛋白的紫杉醇抗性细胞中表现出强大的细胞毒活性。相比之下，艾日布林（eribulin）是一种微管去稳定剂，主要通过结合β-微管蛋白上的长春花结构域来终止原丝伸长，从而导致微管灾难。c）抗代谢物卡培他滨是5-氟尿嘧啶 (5-FU) 的前体药物，首先在肝脏中被羧酸酯酶和胞苷脱氨酶代谢为 5'-脱氧-5-氟尿苷 (5'DFUR)。5'DFUR通过胸苷磷酸化酶 (TP) 和/或尿苷磷酸化酶 (UP) 转化为5-FU。鉴于肿瘤组织中TP和UP的浓度明显高于正常组织 ，5-FU的形成和随后产生的活性代谢物优先出现在肿瘤组织中。 这些代谢物最终通过减弱胸苷酸合酶活性（通过FdUMP）并将碱基类似物掺入 RNA（通过FUTP）和DNA（通过FdUTP）而导致细胞损伤。d）DNA拓扑异构酶抑制剂表柔比星是蒽环类抗生素多柔比星的 4'-差向异构体，至少表现出等效的细胞毒性，但骨髓毒性低于多柔比星。它与拓扑异构酶‍ IIα (TOP2A) 结合，后者会干扰解旋酶活性和 TOP2A- DNA可裂解复合物的形成，导致不可逆的 DNA 双链断裂 (DSB) 和基因转录抑制。e）芳香化酶抑制剂在绝经前妇女中，雌激素主要在卵巢中合成。然而，在绝经后妇女中，雌激素是在脂肪组织、乳房和皮肤中合成的，而这个过程是由芳香酶介导的。芳香酶将卵巢和肾上腺释放的雄烯二酮和睾酮分别转化为雌酮 (E1) 和 E2。 基于此开发了三种第三代芳香化酶抑制剂，用于患有ER阳性乳腺癌的绝经后妇女 。可逆性非甾体芳香酶抑制剂阿那曲唑（anastrozole）和来曲唑（letrozole）是三唑衍生物，通过与芳香酶的血红素辅基结合发挥临床疗效。相反，不可逆的芳香酶灭活剂依西美坦（exemestane）与芳香酶的底物结合袋结合，导致其降解。f）ER抑制剂托瑞米芬是一种结构类似于他莫昔芬的 SERM，仅与一个氯原子不同 。与他莫昔芬一样，托瑞米芬通过竞争性抑制雌二醇 (E2) 与 ER 的结合发挥药理活性。因此，由于相似的药理学机制，它不能用作他莫昔芬失败后的二线治疗。相比之下，氟维司群是一种完整的 ER 拮抗剂，被批准为 SERD，可克服他莫昔芬和托瑞米芬的激动作用。然而，由于其较差的理化特性，氟维司群必须每月肌肉注射一次，限制了其临床应用。g）CDK4/6抑制剂细胞周期蛋白D-细胞周期蛋白依赖性激酶 4/6 (CDK4/6) 和CDK4/6诱导的视网膜母细胞瘤 (RB) 磷酸化的形成是细胞周期中G1-S期转变的核心事件。抑制CDK4/6可诱导RB低磷酸化和再激活，从而导致稳定的细胞周期停滞在G1期。三款CDK4/6抑制剂（palbociclib、ribociclib和abemaciclib）已获准与非甾体芳香酶抑制剂联合用于HR+、HER2-乳腺癌患者的一线治疗。尽管三种CDK4/6抑制剂有多种相似之处，但它们各自都存在独特的特征。Palbociclib主要针对CDK4单体而不是内源性CDK4三聚体复合物或CDK6，但会促进无活性CDK2复合物的形成。Palbociclib和ribociclib对CDK4/6的选择性高于abemaciclib，这可能是由于前者具有更高的亲脂性和更大的结合位点侧链，从而降低与脱靶激酶ATP结合口袋的相互作用。h）靶向HER2的单抗曲妥珠单抗（trastuzumab）在与HER2的胞外结构域 IV 的C末端部分结合，并通过ADCC、HER2脱落的抑制和配体非依赖性下游级联破坏等多种机制发挥其功能。然而，曲妥珠单抗不足以阻断配体诱导的HER2/HER3二聚化。相比之下，帕妥珠单抗（pertuzumab）结合HER2的胞外结构域 II 并阻断配体依赖性和配体非依赖性HER2/HER3二聚化和激活。与不含pertuzumab的方案相比，在trastuzumab加多西他赛的组合中加入pertuzumab可显著改善PFS和OS。Margetuximab作为最新批准的HER2单抗，提高了HER2-low肿瘤的 ADCC效应，增强了靶向活性并克服了trastuzumab耐药性。与trastuzumab联合化疗相比，margetuximab联合化疗可显著改善既往接受过两次或两次以上抗HER2治疗的HER2阳性患者的PFS。Trastuzumab可显著改善HER2阳性乳腺癌患者的临床结果。然而，在转移情况下，大多数接受trastuzumab治疗的患者在一年内会出现耐药和疾病进展。Trastuzumab耐药的一般机制是指trastuzumab与HER2相互作用发生障碍、HER2下游信号通路的重新激活、旁路信号通路的启动以及未能触发免疫介导的机制。i）靶向HER2的ADCKadcyla（TDM-1，2013年上市）由trastuzumab和细胞毒素DM1组成，通过不可切割的硫醚linker（SMCC，MCC）连接。DM1是从各种Maytenus物种中分离出来的美登素衍生物，通过破坏微管的稳定性发挥抗肿瘤活性。TDM-1保留了trastuzumab的所有抗肿瘤功效，并且对拉帕替尼耐药的乳腺癌细胞和拉帕替尼不敏感的肿瘤具有活性。TDM-1显示出比拉帕替尼加卡培他滨、曲妥珠单抗加多西紫杉醇更显著的临床优势。尽管取得了这些治疗进展，但大多数接受TDM-1治疗的患者最终都会出现疾病进展。TDM-1的耐药机制与trastuzumab部分重叠，还包括P-糖蛋白过表达和受体介导的内吞作用缺陷。2019年，第三代ADC药物Enhertu（T-DXd，大名鼎鼎的DS-8201）获批上市，DS-8201由曲妥珠单抗和TOP1抑制剂有效载荷（Dxd，一种exatecan衍生物）组成，通过蛋白酶可切割的马来酰亚胺四肽linker连接。DS-8201在先前接受过TDM-1治疗的患者中表现出持久的抗肿瘤活性。j）HER2小分子抑制剂三种HER2抑制剂拉帕替尼（lapatinib）、来那替尼（neratinib）和图卡替尼（tucatinib）被批准作为与曲妥珠单抗和/或卡培他滨联合治疗HER2阳性乳腺癌的三线方案。与HER2单抗相反，HER2抑制剂结合细胞质酪氨酸激酶结构域而不是HER2的胞外区。拉帕替尼是EGFR和HER2双重抑制剂，通过可逆地结合EGFR和HER2的细胞质ATP位点发挥抗肿瘤活性。有趣的是，拉帕替尼还通过直接减弱其转运活性来逆转P-糖蛋白和ABCG2介导的多药耐药性 (MDR) 。k）PARP小分子抑制剂PARP和BRCA是主要的DNA修复蛋白，当同时抑制这两个蛋白时会导致细胞死亡，而单独抑制其中一个则不会，这个现象被称为“合成致死”（synthetic le‍thality）。PARP抑制剂通过合成致死机制导致BRCA1/2突变癌细胞死亡。Olaparib（奥拉帕尼）、rucaparib、niraparib和talazoparib是FDA批准的四款PARP抑制剂，它们的IC50值分别为1.94、1.98、3.8和0.57 nM 。‍l）PI3K-α小分子抑制剂在大约40%的HR+、HER2-乳腺癌中观察到磷脂酰肌醇3-激酶催化亚基A (PIK3CA)基因突变。Alpelisib是PI3K-α抑制剂，与PI3K-α结合在ATP口袋处，从而抑制PI3K-α的酶活性和PI3K-α介导的下游通路。Alpelisib与氟维司群或来曲唑联合治疗HR+、HER2-乳腺癌，在PIK3CA患者中表现出可耐受的安全性和良好的临床疗效。m）靶向Trop-2的ADC滋养层细胞表面抗原-2（Trop-2，也称为EGP-1）是一种跨膜糖蛋白，在 83%的乳腺癌病例和85%的TNBC中过表达。它被认为是人类癌症的关键驱动因素，使其成为TNBC治疗的一个热门靶标 。2020年上市的Trodelvy是一款以Trop-2 ADC，由sacituzumab和SN-38组成，通过可水解的CL2A linker共价连接。Safituzumab是从鼠RS7-3G11开发的人源化Trop-2单抗，SN-38是TOP1抑制剂伊立替康的活性代谢物。与标准化疗相比，Trodelvy在接受重度治疗的转移性TNBC患者中表现出持久的客观反应和显著优势。然而，Trodelvy的临床益处高度依赖于Trop-2的表达，在低Trop-2表达亚组中很难得出明确的结论。参考文献：[1] Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. Journal of Hematology & Oncology 2022.