A Phase II Randomised, Open-label Study of Gemcitabine/Carboplatin First-line Chemotherapy in Combination With or Without the Antisense Oligonucleotide Apatorsen (OGX-427) in Advanced Squamous Cell Lung Cancers

This study is being carried out to see if a new drug called Apatorsen in combination with standard gemcitabine/carboplatin chemotherapy is effective in treating squamous cell lung cancer.
This study is part of a research project for collecting information about the effectiveness and safety of Apatorsen when used with gemcitabine/carboplatin chemotherapy. The main purpose of this study is to see if Apatorsen, when combined with gemcitabine/carboplatin, is an effective treatment for squamous cell lung cancer.
Recent research has found that a protein called Hsp27 can help cancer cells protect themselves against the effects of cancer treatments. Hsp27 is only found in some lung cancers but when it is present, cancer drugs might not work as well as they would without Hsp27 being present. Blocking the action of Hsp27 or removing Hsp27 from cancer cells with Apatorsen may slow down or stop the cancer growing. This study will therefore look at the relationship between the Hsp27 levels in tumour and blood and the effect of the treatment.
The development of Apatorsen is intended to provide a new treatment option for patients with cancer. Apatorsen may also make the cancer more sensitive to gemcitabine and carboplatin and so make this chemotherapy treatment more effective.

开始日期2014-06-01

申办/合作机构

Queen Mary University of London

[+1]

EUCTR2014-000199-25-GB

/ Not yet recruiting临床2期

A Phase II, randomised, open-label study of Gemcitabine/Carboplatin first-line chemotherapy in combination with or without the antisense oligonucleotide Apatorsen (OGX-427) in advanced squamous cell lung cancers - CEDAR

开始日期2014-04-22

申办/合作机构

Queen Mary University of London

NCT01844817

/ Completed临床2期

A Randomized, Double-Blinded, Placebo-Controlled Phase II Trial Of Gemcitabine Plus Nab-Paclitaxel Combined With OGX-427 Or Placebo In Patients With Metastatic Pancreatic Cancer (The Rainier Trial)

The purpose of this study is to compare the overall survival in patients with previously untreated metastatic pancreatic cancer receiving gemcitabine/nab-paclitaxel plus OGX-427 or gemcitabine/nab-paclitaxel plus placebo.

开始日期2013-09-01

申办/合作机构

SCRI Development Innovations, LLC

[+1]

100 项与 Apatorsen 相关的临床结果

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100 项与 Apatorsen 相关的转化医学

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100 项与 Apatorsen 相关的专利（医药）

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项与 Apatorsen 相关的文献（医药）

2023-07-01·The Journal of urology

LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer

Article

INTRODUCTION AND OBJECTIVE::

Within 10 years following definitive therapy for prostate cancer, ∼20–50% of patients (pts) experience biochemical recurrence (BCR) characterized by rising prostate-specific antigen (PSA) levels. Pts with high-risk BCR have an increased risk of mortality and improved therapies are needed. The objective of EMBARK was to evaluate the efficacy and safety of enzalutamide (enza) + androgen deprivation therapy (ADT) and enza monotherapy (mono) in pts with high-risk BCR.

METHODS::

EMBARK is a randomized, phase 3 study of pts with BCR considered high-risk: PSA doubling time ≤9 months and PSA ≥2 ng/mL above nadir post-radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Pts were randomized (1:1:1) to enza 160 mg/day + leuprolide acetate (LA) (double-blind), placebo (pbo) + LA (double-blind), or enza mono (open-label). LA 22.5 mg was administered every 12 weeks. If the PSA at week 36 was <0.2 ng/mL, therapy was stopped at week 37 and restarted when PSA was ≥2 ng/mL for pts with primary RP, and ≥5 ng/mL for pts without RP. The primary endpoint, determined by blinded, independent central review (BICR), was metastasis-free survival (MFS) with enza + LA vs pbo + LA. Key secondary endpoints were MFS of enza mono vs pbo + LA, time to PSA progression, time to antineoplastic therapy, and overall survival (OS) of enza + LA or enza mono vs pbo + LA.

RESULTS::

1068 pts were randomized into the study (enza + LA, n=355; pbo + LA, n=358; enza mono, n=355). After median follow-up of 60.7 months, per BICR, MFS for enza + LA (HR 0.42; 95% CI 0.30–0.61; p<0.0001) and enza mono (HR 0.63; 95% CI 0.46–0.87; p=0.0049) were statistically superior to pbo + LA. Statistically significant improvements were also observed in risk of PSA progression (enza + LA: HR 0.07; 95% CI, 0.03–0.14; enza mono: HR 0.33; 95% CI, 0.23–0.49; both p<0.0001) and time to first use of new antineoplastic therapy (enza + LA: HR 0.36; 95% CI, 0.26–0.49; enza mono: HR 0.54; 95% CI, 0.41–0.71; both p<0.0001). Interim OS data trended in favor enza + LA (HR 0.59; 95% CI, 0.38–0.91; p=0.0153, did not cross interim efficacy boundary) and enza mono (HR 0.78; 95% CI, 0.52–1.17; p=0.2304). Fatigue and hot flash were the most common adverse events; no new safety signals were observed.

CONCLUSIONS::

In pts with high-risk BCR, enza + ADT and enza mono demonstrated a statistically significant and clinically meaningful improvement in MFS vs pbo + ADT. The safety profile of enza was consistent with results from previous clinical studies.

Clinical Trial Registration Number::

NCT02319837.

Source of Funding::

Pfizer Inc. and Astellas Pharma Inc.

Conflict of Interest and Disclosure Statement::

Neal D. Shore reports grant support and consulting fees from AbbVie, Amgen, Astellas Pharma Inc., AstraZeneca, Bayer, Clovis Oncology, Dendreon Pharmaceuticals LLC, Ferring Pharmaceuticals, GenesisCare, Janssen Oncology, Merck, Myovant Sciences, Pfizer Inc., Sanofi-Genzyme, and Tolmar Pharmaceuticals, Inc. Murilo de Almeida Luz reports receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, Merck Sharp & Dohme, and Pfizer Inc.; being an advisory board member for Astellas Pharma Inc., Bayer, and Janssen; sponsored research from Bayer, Bristol Myers Squibb, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen, and Roche; receiving travel expenses from AstraZeneca, Bayer, Janssen, and Pfizer Inc. Ugo De Giorgi reports serving as a consultant for Janssen, Astellas Pharma Inc., Sanofi, Bayer, Pfizer Inc., Bristol Myers Squibb, Novartis, Ipsen, and Merck Sharp & Dohme. Martin Gleave reports stock or ownership interest in OncoGenex Technologies Inc., Sustained Therapeutics Inc., and Sikta Biopharma; is a consultant to Astellas Pharma Inc., AstraZeneca, Bayer, Genova Diagnostics (GDx), Janssen, Pfizer Inc., Roche, Sanofi, and TerSera Therapeutics LLC; and holds patents for OGX-011, OGX-427, ST-CP, and ST-POP. Geoffrey T. Gotto reports receiving honoraria from Amgen, Astellas Pharma Inc., Bayer, Ferring Pharmaceuticals, Janssen, and Merck; being a consultant or advisory board member for Amgen, Astellas Pharma Inc., Bayer, Janssen, and Merck; providing expert testimony for Janssen; and receiving support for travel, accommodation, and expenses from Janssen. Gabriel P. Haas reports being an employee of and shareholder in Astellas Pharma Inc. Miguel Ramirez-Backhaus reports serving as a consultant or advisory board member for Astellas Pharma Inc., Bayer, Janssen, and Karl Storz; receiving speaker honoraria from Astellas Pharma Inc., Bayer, Janssen, and GP Pharm. Antti Rannikko reports being a board member for the Ida Montin Foundation, and Orion Research Foundation; being an advisory board member for Bayer, Janssen, and Orion Pharma; being a stockholder and clinical advisor for Aqsens Health; being a clinical investigator for Astellas Pharma Inc., Bayer, Janssen, Orion Pharma, and RhoVac AB; and receiving competitive state research funding from HUS Helsinki University Hospital, Finnish Cancer Organizations, and the Jane and Aatos Erkko Foundation. Jamal Tazari, Yiyun Tang, and Fabian Zohren are employees of and shareholders in Pfizer Inc. Swetha Sridharan reports no conflicts of interest. Jennifer Sugg is an employee of Astellas Pharma Inc., and a shareholder in AstraZeneca. Ronald F. Tutrone, Jr. reports being an advisory board member for Bayer; and receiving speaker honoraria from Astellas Pharma Inc., Exosome Diagnostics, Inc., Myovant Sciences, and Pfizer Inc. Balaji Venugopal reports receiving honoraria from Bristol Myers Squibb, Eisai Co., Ltd, EUSA Pharma, Ipsen, Janssen, and Merck; being a consultant or advisory board member for Janssen, Merck Sharp & Dohme Oncology, and Pfizer Inc./EMD Serono; and receiving support for travel, accommodation, and expenses from EUSA Pharma, and Ipsen. Arnauld Villers reports receiving research grants from Astellas Pharma Inc., Ferring Pharmaceuticals, Ipsen, and Janssen. Henry H. Woo reports being an advisory board member for Astellas Pharma Inc., Bayer, Boston Scientific Corporation, and Mundipharma International Ltd; and reports receiving speaker honoraria from AbbVie, Astellas Pharma Inc., Boston Scientific Corporation, and Janssen. Stephen J. Freedland reports being a consultant for Astellas Pharma Inc., AstraZeneca, Bayer, Dendreon Pharmaceuticals LLC, Janssen, Merck, Myovant Sciences, Pfizer Inc., and Sanofi.

Acknowledgments::

The authors thank all the patients, their families, and the investigators and investigational site members involved in this study.

Editorial Acknowledgement::

Medical writing and editorial support was provided by Julie B. Stimmel, PhD, Sinead Stewart, and Rosie Henderson, of Onyx (a Prime Global Agency), funded by Pfizer, Inc. and Astellas Pharma Inc., the co-developers of enzalutamide.

Submission Category::

prostate cancer.

Sub-category::

Advanced (including drug therapy).

2023-02-01·Molecular therapy : the journal of the American Society of Gene Therapy

DDX5 mRNA-targeting antisense oligonucleotide as a new promising therapeutic in combating castration-resistant prostate cancer

Article

作者: Cherif, Chaïma ; Audebert, Stéphane ; Taïeb, David ; Paris, Clément ; Baudelet, Emilie ; Fazli, Ladan ; Gleave, Martin ; Bertucci, François ; Bastide, Cyrille ; Lannes, François ; Finetti, Pascal ; Hamimed, Mourad ; Le, Thi Khanh ; Rocchi, Palma ; Omabe, Kenneth ; Barbolosi, Dominique

The heat shock protein 27 (Hsp27) has emerged as a principal factor of the castration-resistant prostate cancer (CRPC) progression. Also, an antisense oligonucleotide (ASO) against Hsp27 (OGX-427 or apatorsen) has been assessed in different clinical trials. Here, we illustrate that Hsp27 highly regulates the expression of the human DEAD-box protein 5 (DDX5), and we define DDX5 as a novel therapeutic target for CRPC treatment. DDX5 overexpression is strongly correlated with aggressive tumor features, notably with CRPC. DDX5 downregulation using a specific ASO-based inhibitor that acts on DDX5 mRNAs inhibits cell proliferation in preclinical models, and it particularly restores the treatment sensitivity of CRPC. Interestingly, through the identification and analysis of DDX5 protein interaction networks, we have identified some specific functions of DDX5 in CRPC that could contribute actively to tumor progression and therapeutic resistance. We first present the interactions of DDX5 and the Ku70/80 heterodimer and the transcription factor IIH, thereby uncovering DDX5 roles in different DNA repair pathways. Collectively, our study highlights critical functions of DDX5 contributing to CRPC progression and provides preclinical proof of concept that a combination of ASO-directed DDX5 inhibition with a DNA damage-inducing therapy can serve as a highly potential novel strategy to treat CRPC.

2019-12-01·The oncologist2区 · 医学

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial

2区 · 医学

Article

作者: Shipley, Dianna L. ; Spigel, David R. ; Hainsworth, John D. ; Waterhouse, David M. ; Page, Ray D. ; Jones, Suzanne F. ; Mekhail, Tarek ; Jacobs, Cindy ; Ward, Patrick J. ; Hemphill, Brian ; Shih, Kent C. ; Burris, Howard A. ; McCleod, Michael ; Whorf, Robert C. ; Stilwill, Joseph

Abstract:

Background:

Methods:

Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity.

Results:

The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months.

Conclusion:

The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

Implications for Practice:

This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

项与 Apatorsen 相关的新闻（医药）

2023-05-09

·药时代

RNA疗法一路“狂飙”，下一个重磅炸弹的掘金之地？

来源：药渡撰文：雨巷少年编辑：丸子众所周知，癌症是一个无法攻克的挑战，目前还没有特效药可以完全治愈。近年来，随着生物制药领域的发展，癌症治疗的研究方向逐渐转向RNA疗法，包括寡核苷酸药物和mRNA疫苗等。通常，常规治疗只会产生短暂的治疗效果，因为它们针对的是蛋白质而不是致病根源，而RNA疗法直接作用于致病靶基因或者靶mRNA，在基因水平上发挥治疗疾病的作用。RNA疗法具有治疗效率高、药物毒性小、特异性强和应用领域广等优点，在医学、生命科学等领域表现出巨大的前景。1RNA疗法及其研发现状目前，癌症治疗在世界范围内仍然是一个挑战。虽然通过手术切除肿瘤组织、化疗和放疗可以提高患者的总体生存期，但癌症的复发和转移是无法避免的。此外，化疗具有严重的不良反应，如全身毒性和多重耐药，这就需要开发新型有效的治疗药物。近年来，靶向肿瘤细胞内或细胞外蛋白质的小分子药物和抗体因其强大的抗肿瘤作用而越来越受欢迎。然而，它们针对转录因子和“不可成药”癌蛋白等靶点却显得束手无策，如RAS等。理论上，RNA疗法可以特异性靶向和沉默任何基因靶点。因此，在针对“不可成药”靶点无药可用的问题方面具有巨大优势。随着RNA技术的不断发展和改进，许多寡核苷酸药物和大分子RNA药物，如反义寡核苷酸(ASOs)、小干扰RNA (siRNAs)和mRNA疫苗已被批准上市(图1)。此外，越来越多的寡核苷酸药物(如ASOs、siRNAs和miRNAs)和mRNA药物正在全球范围内进入临床试验。目前RNA疗法已成为癌症治疗的潜在候选工具。图1.已上市的核酸药物2RNA疗法潜力赛道：寡核苷酸疗法寡核苷酸是由10-50个核苷酸组成的药物，包括ASOs、siRNA和microRNAs (miRNAs)。寡核苷酸可以通过与特定的DNA或RNA序列或蛋白质结合并干扰靶基因表达来治疗疾病。它们可以调节转录后水平，并有望靶向难以直接靶向的特殊靶点。因此，寡核苷酸被认为是继小分子药物和抗体之后的第三大类型药物。目前，ASOs、siRNAs和miRNAs是研究最广泛的治疗恶性肿瘤的寡核苷酸药物。1反义寡核苷酸（ASO）ASOs是通过化学合成的寡核苷酸，通常长度为1-30个核苷酸，遵循沃森-克里克碱基配对规则与RNA结合。ASOs的长度允许它们只能与一个靶RNA结合。因此，ASOs具有高度特异性和专一性。尽管前两种上市的ASO药物Fomivirsen和Mipomersen已经停产，但市场上仍有7种被批准用于医疗用途的ASO药物，用于治疗杜氏肌营养不良症(DMD)、脊髓性肌萎缩、家族性淀粉样蛋白多神经病、家族性乳糜少血症综合征等疾病（图1））。在过去数十年来，大量制药大厂布局ASO药物。目前，ASO在合成和配方以及分布和安全性方面取得了令人满意的进展已有多种ASOs药物开展临床试验（图2）。图2.开展临床试验的ASO药物接下来介绍一些重点ASO药物：2.1.1 Oblimersen sodium (Genasense™, G3139)Oblimersen钠(Genasense™，G3139)是一种反义寡核苷酸，与Bcl-2 mRNA开放阅读框的前六个密码子杂交，导致Bcl-2 mRNA降解并诱导细胞凋亡。oblimersen联合化疗药物如卡铂、紫杉醇、多西他赛、伊立替康等治疗实体肿瘤已开展了较多临床试验。在I/II期试验中，转移性结直肠癌患者对oblimersen和前药伊立替康的联合耐受性良好；其中，1例患者出现部分缓解，另外10例患者病情稳定，持续2.5-10个月(NCT00004870)。此外，临床试验的安全性数据进一步支持oblimersen联合细胞毒性药物临床开发的可行性。2.1.2 BP1001BP1001是一种脂质体结合的反义寡核苷酸，旨在抑制生长因子受体结合蛋白-2 (Grb-2)的表达，Grb-2是癌细胞信号传导中的一种必要的癌蛋白。在I期临床研究(NCT01159028)中，BP1001作为单药治疗和与低剂量ala - c (LDAC)联合使用都具有良好的耐受性。2.1.3 OGX-011 (custirsen)OGX-011 (custirsen)是第二代反义聚集蛋白抑制剂。为了确定OGX-011的临床活性，一项随机II期研究多西他赛/强的松联合用药用于治疗转移性去势抵抗性前列腺癌患者。研究结果表明OGX-011和多西他赛治疗耐受性良好，且与生存率提高有关，因为OGX011可以通过增加肿瘤细胞对多西他赛的敏感性来增强肿瘤杀伤能力。因此，OGX-011也可能是去势抵抗性前列腺癌(CRPC)患者的一种新的治疗策略。2.1.4 OGX-427OGX-427 (Apatoren)是一种2 ' -甲氧基修饰的ASO，可抑制Hsp27的表达。热休克蛋白27 (Hsp27)是一种应激诱导的多功能伴侣，通过其增殖和抗凋亡功能促进癌症的发展。Hsp27参与内质网(ER)稳态，使用OGX-427敲除Hsp27可诱导内质网应激。在I期临床试验中，OGX-427在晚期癌症患者中的安全性显示，OGX-427在最高剂量(1000 mg)下耐受(NCT00487786)。2.1.5 AZD9150 (Danvatirsen, ISIS 481464)AZD9150 (danvatersen, ISIS 481464)， 2.5代ASO，是STAT3的特异性抑制剂。与2.0代和以前的ASOs相比，2.5代ASOs具有更高的亲和性和更强的内在效力。AZD9150可以特异性抑制STAT3并诱导多种白血病细胞系凋亡。此外，AZD9150还通过抑制内源性STAT3和STAT3靶基因，降低成神经细胞瘤细胞的致瘤性，增加细胞的化学敏感性。在两项I期临床研究(NCT01563302和NCT01839604)中，AZD9150单药治疗诱导了免疫介导的抗肿瘤反应，表明AZD9150联合免疫检查点抑制剂治疗有望增强抗肿瘤免疫效能。2.1.6 EZN-2968缺氧诱导因子-1 (HIF-1)是一种转录因子，在血管生成、存活、转移、耐药和葡萄糖代谢中起关键作用。研究表明，HIF-1高水平与实体瘤患者预后差、耐药有关。因此，HIF-1是癌症治疗的一个有吸引力的靶点。EZN-2968(RO7070179)是第三代ASO，专门针对HIF-1的一个亚基HIF-1α。EZN-2968在临床前模型中与HIF-1α 的mRNA杂交并阻断HIF-1α蛋白表达。EZN-2968在描述剂量和时间下耐受性良好，且大多数报告的毒性为1或2级，无意外毒性。2小干扰RNA（SiRNA）自RNA干扰技术(RNAi)的发现及其随后在哺乳动物细胞中基因敲除的应用以来，siRNA治疗取得了显著的进展，已成为治疗各种疾病的有力工具。作为一种非编码双链RNA (dsRNA)分子，siRNAs的长度只有18-25个碱基对。siRNA在转录后通过mRNA降解干扰具有互补核苷酸序列的特定基因的表达。迄今为止，已有四种siRNA药物(patisiran、givosiran、lumasiran和inclisiran)被批准上市，用于治疗TTR、急性肝性卟啉症、原发性高草酸尿症1型、高胆固醇血症。相较于传统药物，siRNA疗法具有以下几大优势：1、siRNA可以敲除直接或间接导致癌细胞异常增殖的基因。2、大量siRNA文库的可用，可以快速筛选和优化出对靶点具有高度选择性和特异性的SiRNA先导化合物。3、siRNA药物的合成和生产成本与抗体相比相对较低。4、优化的siRNA药物可以提供更方便的给药方案。这些优势有力地支持了siRNA作为治疗癌症关键的治疗工具之一的观点，推动更多siRNA药物进入临床试验（图3）。图3.已进入临床阶段的SiRNA接下来介绍一些重点siRNA药物：2.2.1 CALAA-01CALAA-01是一种基于聚合物的纳米颗粒，含有靶向核糖核酸还原酶(RRM2) M2亚基的siRNA，是Calando制药公司于2008年筛选的第一种基于RNAi技术的实体肿瘤药物。I期临床试验表明，CALAA-01在静脉注射给药后很快在血液中被清除，并且清除与体重有关。2.2.2 Atu027另一种siRNA药物是Atu027，它被包裹在脂质纳米颗粒(LNP)中，可以特异性靶向致癌靶点PKN3。临床试验结果表明，Atu027在晚期或转移性胰腺腺癌患者联合标准化疗药物吉西他滨(NCT00938574)时具有良好的安全性和活性。2.2.3 siG12D LODERsiG12D LODER是一种局部长效SiRNA递送系统，用于针对突变型的KRAS蛋白。一项I期研究显示siG12D LODE在胰腺癌患者中的良好的耐受性、安全性和有效性，并且无明显毒性。目前，siG12D LODER正在进行II期临床试验。这种siRNA药物为抑制KRAS在胰腺癌中的表达提供了另一种方法。2.2.4 DCR-MYCMYC癌基因家族，由C-MYC、MYCN和MYCL组成，其产物调控至少15%的全基因组转录，并参与许多实体肿瘤恶性肿瘤的生长。siRNA药物DCR-MYC由DiceRNA Pharma设计，是一种新型合成的稳定脂质颗粒悬浮液dsRNA，可靶向肝癌、实体瘤和多发性骨髓瘤中的MYC。I期研究表明，DCR-MYC可有效抑制实体瘤患者的肿瘤生长(NCT02110563)。2.2.5 NU-0129由于很多药物不能有效透过血脑屏障BBB，因此胶质母细胞瘤(GBM)一度被认为是最难治疗的癌症之一。NU-0129基于球形核酸类型，是一种靶向GBM癌基因Bcl2L12的siRNA药物，可穿越血脑屏障，可能是治疗GBM的新策略。在早期I期试验中，静脉注射NU-0129后，肿瘤组织中的Bcl2L12蛋白水平显著降低。3miRNA药物miRNA是内源性基因编码的一类小的非编码RNA，大小约为19-25个核苷酸，参与转录后基因表达的调控。通常情况下，一旦miRNAs与RISC结合形成基因沉默复合物miRISC，相对基因表达就会通过基于RISC的机制通过阻断翻译或切割mRNA，这与siRNA机制相类似。值得注意的是，虽然siRNA和miRNA都是非编码RNA，在基因沉默和调控方面的作用相似，但siRNA在特定位置与单个基因完全互补，而一个miRNA通常具有多个靶点，可以调节数百或数千个基因的表达。并且，一个基因可以被几种不同的miRNA调控。尽管大量资本涌入miRNA赛道，但由于安全性问题，许多miRNA药物大多被终止，没有候选药物进入III期临床试验（图4）。因此，解决miRNA药物的特异性问题可以提高miRNA在临床中应用价值。图4.已进入临床试验的miRNA在过去的二十年中，miRNA与各种癌症之间的关系得到了广泛的研究。目前，基于miRNA的疗法有两种策略:miRNA模拟物和miRNA抑制剂，这取决于是否应该替换或下调miRNA以控制细胞中靶mRNA的数量。miRNA mimics是人工合成的双链寡核苷酸，可以过表达相应的内源性miRNA序列，模拟靶miRNA的功能，导致癌细胞增殖下调，从而促进mRNA抑制。与miRNA模拟物不同，miRNA抑制剂（Anti-miRNAs）为基于ASOs生成的互补单链RNA类似物，以靶向内源性miRNA。Anti-miRNAs可以特异性阻断与癌症发展相关的miRNAs的上调表达。2.3.1MRX34作为一种潜在的肿瘤抑制miRNA, miR-34a在干细胞和晚期肿瘤中表达匮乏。MRX34是一种可以与miR-34a模拟物结合的脂质纳米颗粒LNP。MRX34可以通过抑制非小细胞肺癌(NSCLC)小鼠模型中的DNA修复功能来增强放疗的效果。2.3.2 Cobomarsen (MRG-106)研究表明，miR-155血液系统恶性肿瘤中是一种被广泛研究的miRNA，它主要与淋巴瘤和白血病的不良预后相关。Cobomarsen (MRG-106)是一种miR-155的抑制剂，目前正在进行临床试验，研究发现Cobomarsen在体外可以抑制miR-155的下游靶点及其介导的信号通路，包括JAK/STAT、MAPK/ ERK和PI3K/AKT等。2.3.3 Remlarsen (MRG-201)Remlarsen (MRG-201)是一种 miR-29模拟物，目前正在对其进行研究，以确定它是否可以抑制瘢痕疙瘩中纤维性瘢痕组织的形成。一项研究发现miR-29高表达可调控STAT3信号通路，抑制子宫平滑肌瘤的增殖、侵袭和转移;因此，miR-29可能是治疗子宫平滑肌瘤的一个新靶点。3RNA疗法的递送策略目前，递送问题是RNA疗法的最大问题之一。特别是如何安全、高效和有针对性地递送RNA药物仍然是一个重大挑战。核酸药物稳定性差（核酸酶降解）、透膜性差（核酸药物高度负电性）。因此，合适的递送系统可以保护RNA结构不被降解，提高靶向能力，减少毒副作用。目前，RNA疗法主要有三种病毒递送载体:腺病毒(AdV)、腺相关病毒(AAV)和慢病毒。然而，病毒载体具有毒性问题，并且由于其炎症和免疫原性作用而对人类不安全，这限制了它们的临床转化。与病毒载体相比，非病毒载体具有更广泛的应用范围，并克服了成本高、免疫原性和毒性等问题。因此，相对安全的非病毒载体，如基于脂质的递送系统、基于聚合物的纳米颗粒和无机纳米颗粒正在迅速发展（图5）。图5.已报道的核酸药物递送系统1脂质递送系统脂质递送系统，如胶束、脂质体和LNP。其中，LNPs是寡核苷酸药物和mRNA疫苗最广泛使用的非病毒传递系统之一，其优点包括易于生产，可生物降解，保护嵌入的RNA免受核酸酶RNAse的降解和肾脏清除，促进细胞摄取和内体逃逸。近年来LNP作为mRNA疫苗的递送载体受到了全球的关注，在有效保护mRNA并将其转运到细胞中发挥着关键作用。2聚合物递送系统聚合物是继脂类递送系统之后的第二大核酸递送载体。阳离子聚合物可与阴离子核酸形成稳定的复合物，为高效的核酸递送提供了一个多功能、可扩展和易于适应的平台，同时最大限度地减少免疫反应和细胞毒性。这些递送体系可以增加RNA进入细胞的效率，并提高药物稳定性。3无机纳米递送系统无机纳米载体因其稳定性高、生物相容性好、免疫原性低、量产性好等特点，为核酸药物有效递送肿瘤细胞提供了独特的平台，如金纳米颗粒、二氧化硅纳米颗粒、碳纳米管等。总的来说，病毒载体比非病毒传递系统更有效，但更具有免疫原性。非病毒基因载体是通用的、简单的、具有成本效益的和潜在的更安全的替代品，但可能缺乏足够的临床效果。因此，在选择RNA药物的递送载体时，需要考虑多方面的因素，选择最合适的给药载体，以达到最大的疗效和最小的副作用。4小结近年来，由于寡核苷酸药物和mRNA疫苗的成功商业化，在医药圈掀起了一波核酸药物的研发热潮。目前的RNA疗法在疾病诊断和治疗方面都发挥着重要作用。尽管RNA疗法取得了巨大的进展，但临床应用方面仍然面临多种挑战:药物靶点的确定、核酸药物的稳定性和递送问题。通常，靶点和给药途径的选择可以提高药物的疗效，同时减少正常组织的副作用，增加药物的安全性。随着研究人员对多种类型RNA功能的深入了解，有望诞生出具有更高稳定性和药物活性的RNA药物以及更好的核酸递送载体。我们相信，RNA疗法有望改变人类癌症治疗的格局，使更多癌症患者获益。参考文献1、Cancer statistics, 2021[J]. CA: Cancer J Clin. 2021;71(1):7.2、Research progress on non-protein-targeted drugs for cancer therapy. https://doi.org/10.1186/s13046-023-02635-y3、RNA-based drugs and vaccines[J]. Expert Rev Vaccines. 2015;14(2):253–63.4、Deliver the promise: RNAs as a new class of molecular entities for therapy and vaccination[J]. Pharmacol Ther. 2022;230:107967.5、Current advances in RNA therapeutics for human diseases[J]. Int J Mol Sci. 2022;23(5):2736封面图来源：123rf2023年1月1日至今，~17笔中国新药出海交易横空出世，总金额高达上百亿美元！一时间，喜讯频传，令行业、企业和每一位同药振奋！曾经提出“百靶竞技，百炼创新，百家上市，百药争先”的药时代团队再一次真切感受到：中国新药研发正当时！中国新药出海正当时！中国新药BD正当时！在这个BD如火如荼的好时代里，企业对于BD的要求不断提高，如何与时俱进，学习最新BD知识，掌握最新BD技能，成为摆在每一位BD同药面前的一个实际而迫切的问题。为了帮助企业培养优秀的BD高级人才，为了帮助BD人才成长进步，药时代学苑全力打造创新药BD高级研讨会，致力于成为中国制药界ZUI有实力和活力的学习平台。药时代BD高阶研讨会火热报名中！

寡核苷酸信使RNA上市批准核酸药物siRNA

2007-03-08

·BioSpace

OncoGenex Technologies Inc. Withdraws Initial Public Offering

VANCOUVER, March 7 /PRNewswire/ - OncoGenex Technologies Inc. announced today that the company has withdrawn its registration statement from the U.S. Securities and Exchange Commission, citing market conditions as a deterrent to completing its initial public offering. "Due to the recent adverse market conditions, we have decided not to move forward with an initial public offering at this time," stated Scott Cormack, President and Chief Executive Officer of OncoGenex. "We anticipated pricing our initial public offering on February 27, coincidentally the same day that the equity markets suffered the largest one-day decline in four years. Given current market conditions, we believe it is in our shareholders' best interest to withdraw our initial public offering and continue to focus on delivering results from our phase 2 programs. "We have the resources to complete our five ongoing phase 2 clinical trials with our lead product candidate, OGX-011, in prostate, breast and non-small cell lung cancers," added Cormack. "We expect to have primary endpoint data from all five of these trials by the end of this year, and we look forward to reporting data in the appropriate forums." About OncoGenex OncoGenex is committed to the development and commercialization of new cancer therapies that address treatment resistance in cancer patients. OncoGenex currently has three product candidates in development: OGX-011, OGX-427 and OGX-225. These product candidates are designed to selectively inhibit the production of proteins that are associated with treatment resistance and that are over-produced in response to a variety of cancer treatments. OncoGenex' aim in targeting these particular proteins is to disable the tumor cells' adaptive defenses, render the tumor cells susceptible to attack with a variety of cancer therapies including chemotherapy, and facilitate tumor cell death. More information on OncoGenex and the company's pipeline is available at . Forward-looking Statements This press release may include forward-looking statements. Statements regarding future events, expectations and beliefs of management and other statements that do not express historical facts, are forward-looking statements. Words such as "believe", "may", "will", "estimate", "continue", "anticipate", "intend", "expect", "plan", "predict", "potential" and similar expressions, as they relate to OncoGenex, our business and our management, are intended to identify forward-looking statements. We have based these forward-looking statements largely on our current expectations and projections about future events and financial trends affecting the financial condition of our business. Forward-looking statements should not be read as a guarantee of future performance or results, and will not necessarily be accurate indications of the times at, or by, which such performance or results will be achieved. Forward-looking statements are based on information available at the time those statements are made and/or management's good faith belief as of that time with respect to future events, and are subject to risks and uncertainties that could cause actual performance or results to differ materially from those expressed in or suggested by the forward-looking statements. Important factors that could cause such differences include, but are not limited to: delays or unfavorable results from our current and planned clinical trials; our ability to establish and maintain intellectual property protection for our product candidates; our access to additional capital; our ability to enter into and maintain relationships with third parties, such as licensors, manufacturers, suppliers and those who conduct clinical trials for us; our ability to enroll patients for our clinical trials; our ability to implement and manage our sales and commercialization initiatives; the impact of competition and technological change; the timing of necessary regulatory clearances; coverage and reimbursement policies of governmental and private third-party payors, including the U.S. Medicare and Medicaid programs; general economic and business conditions, both nationally and in our markets; our ability to attract and retain key management and scientific personnel; existing and future regulations that affect our business; and other factors included in OncoGenex's filings with the United States Securities and Exchange Commission and the Canadian securities regulators. In light of these risks and uncertainties, forward-looking events and circumstances included in this presentation may not occur and actual results could differ materially from those anticipated or implied in the forward-looking statements. Forward-looking statements speak only as of the date the statements are made. You should not put undue reliance on any forward-looking statements. We assume no obligation to update forward-looking statements to reflect actual results, changes in assumptions or changes in other factors affecting forward-looking information, except to the extent required by applicable securities laws. If we do update one or more forward-looking statements, no inference should be drawn that we will make additional updates with respect to those or other forward-looking statements. CONTACT: OncoGenex Contact: Scott Cormack, President & CEO, (604) 630-5400, scormack@oncogenex.ca; Media Contact: Jason Spark, Porter Novelli Life Sciences, (619) 849-6005, jspark@pnlifesciences.com OncoGenex Technologies Inc. CONTACT: OncoGenex Contact: Scott Cormack, President & CEO, (604)630-5400, scormack@oncogenex.ca; Media Contact: Jason Spark, Porter NovelliLife Sciences, (619) 849-6005, jspark@pnlifesciences.com >>> Discuss This Story

IPO

100 项与 Apatorsen 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06094

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
晚期鳞状细胞肺癌	临床2期	英国	Achieve Life Sciences, Inc.	2014-06-01
转移性胰腺癌	临床2期	美国	Achieve Life Sciences, Inc.	2013-09-01
晚期肺非鳞状非小细胞癌	临床2期	美国	Achieve Life Sciences, Inc.	2013-07-01
转移性非小细胞肺癌	临床2期	美国	Achieve Life Sciences, Inc.	2013-07-01
非鳞状非小细胞肺癌	临床2期	美国	Achieve Life Sciences, Inc.	2013-07-01
复发性膀胱癌	临床2期	美国	Achieve Life Sciences, Inc.	2013-04-01
膀胱尿路上皮癌	临床2期	美国	Achieve Life Sciences, Inc.	2013-04-01
复发性尿路上皮癌	临床2期	美国	Achieve Life Sciences, Inc.	2013-04-01
转移性去势抵抗性前列腺癌	临床2期	美国	Achieve Life Sciences, Inc.	2012-12-01
转移性去势抵抗性前列腺癌	临床2期	加拿大	Achieve Life Sciences, Inc.	2012-12-01

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临床结果

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分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01829113 (SPRUCE, Pubmed \| Oncologist) 人工标引	临床2期	非鳞状非小细胞肺癌一线	155	Carboplatin+Pemetrexed+Apatorsen	艱鏇範構糧餘築願壓艱(願艱襯範範夢構遞蓋鑰) = 願鬱選鏇憲構齋顧繭壓遞鑰鑰醖醖艱積鬱衊蓋 (鏇膚願壓憲遞艱鏇繭窪 ) 更多	不佳	2019-12-01
				Carboplatin+Pemetrexed+Placebo	艱鏇範構糧餘築願壓艱(願艱襯範範夢構遞蓋鑰) = 鬱窪顧齋糧網艱襯獵顧遞鑰鑰醖醖艱積鬱衊蓋 (鏇膚願壓憲遞艱鏇繭窪 ) 更多
NCT01681433 (GU12-159, CTgov)	临床2期	涎腺多形性腺瘤 \| 转移性去势抵抗性前列腺癌	72	OGX-427+prednisone+Abiraterone Acetate (Experimental: Arm A)	艱獵餘襯鑰膚鹽憲選構 = 餘選窪製鏇壓觸醖範夢糧顧簾憲壓顧簾觸淵鏇 (製蓋廠獵顧觸淵構齋簾, 構糧遞夢糧繭獵夢築窪 ~ 艱鑰糧鏇襯築鑰廠築範) 更多	-	2018-10-18
				prednisone+Abiraterone Acetate (Control Arm: Arm B)	艱獵餘襯鑰膚鹽憲選構 = 網餘糧衊網餘選蓋網夢糧顧簾憲壓顧簾觸淵鏇 (製蓋廠獵顧觸淵構齋簾, 獵築簾艱膚窪鏇簾鬱齋 ~ 糧範膚簾衊鑰窪鏇餘範) 更多
NCT01829113 (SPRUCE, CTgov)	临床2期	转移性非小细胞肺癌 \| 晚期肺非鳞状非小细胞癌 \| 非鳞状非小细胞肺癌	155	OGX-427 (OGX-427)	獵窪淵獵範憲膚壓鹽鏇(鹹餘願鏇鏇淵範憲鬱淵) = 鏇夢鹹膚範艱窪窪艱艱鏇衊廠蓋遞願憲蓋築製 (襯窪範構壓壓選鑰範積, 壓憲繭夢獵觸積夢築膚 ~ 蓋艱鹽襯膚製餘齋積鏇) 更多	-	2018-06-08
				Placebo (Placebo)	獵窪淵獵範憲膚壓鹽鏇(鹹餘願鏇鏇淵範憲鬱淵) = 襯網觸選鹹襯繭憲鏇鏇鏇衊廠蓋遞願憲蓋築製 (襯窪範構壓壓選鑰範積, 積觸積繭壓鑰憲構鬱構 ~ 遞衊網餘鑰夢願構齋鏇) 更多
NCT01780545 (Borealis-2, Pubmed) 人工标引	临床2期	转移性尿路上皮癌	200	docetaxel+Apatorsen	淵顧鏇齋憲製餘糧窪繭(範糧廠艱鏇鏇鹹鹹製網) = 鹹淵壓憲範繭網積鑰壓鑰築蓋顧醖齋廠簾築簾 (蓋觸製構觸鹹餘築窪範 )	积极	2018-05-01
				docetaxel	淵顧鏇齋憲製餘糧窪繭(範糧廠艱鏇鏇鹹鹹製網) = 獵夢餘築範鏇夢艱鏇築鑰築蓋顧醖齋廠簾築簾 (蓋觸製構觸鹹餘築窪範 )
NCT01120470 (Pubmed) 人工标引	临床2期	转移性去势抵抗性前列腺癌	74	apatorsen+prednisone	選鹽夢願膚獵淵憲糧醖(製蓋築餘鑰選糧遞觸齋) = 窪鑰遞網積繭廠壓選網積鹽簾憲蓋鹽憲遞鹹簾 (夢餘憲顧廠選築襯獵壓, 32.9 ~ 67.1) 更多	积极	2018-04-01
				prednisone	選鹽夢願膚獵淵憲糧醖(製蓋築餘鑰選糧遞觸齋) = 築築構鬱壓網鏇築廠醖積鹽簾憲蓋鹽憲遞鹹簾 (夢餘憲顧廠選築襯獵壓, 26.3 ~ 59.2) 更多
NCT01844817 (RAINIER, Pubmed \| Oncologist) 人工标引	临床2期	转移性胰腺癌一线	132	Gemcitabine+Nab-Paclitaxel+Apatorsen	憲糧鹽壓餘窪壓襯鹽鬱(齋襯鏇醖築願壓製壓鹹) = 鏇範襯鏇願構觸憲願鑰衊鹹築醖選構襯壓遞糧 (顧壓觸壓鏇壓鏇願廠簾 ) 更多	不佳	2017-12-01
				Gemcitabine+Nab-Paclitaxel+Placebo	憲糧鹽壓餘窪壓襯鹽鬱(齋襯鏇醖築願壓製壓鹹) = 鹹壓襯憲廠願鹹衊膚獵衊鹹築醖選構襯壓遞糧 (顧壓觸壓鏇壓鏇願廠簾 ) 更多
NCT01844817 (RAINIER, CTgov)	临床2期	转移性胰腺癌	132	OGX-427 (OGX-427)	憲範醖網壓構遞廠糧獵(簾遞顧餘繭構範鬱繭積) = 鑰顧壓憲觸鹹淵範選襯選積積衊觸衊膚製憲壓 (醖糧襯獵鹽艱獵壓夢窪, 壓齋鬱窪觸艱鹹壓夢觸 ~ 簾願獵憲範範顧顧蓋獵) 更多	-	2017-05-16
				Placebo (Placebo)	憲範醖網壓構遞廠糧獵(簾遞顧餘繭構範鬱繭積) = 餘觸鏇憲範網窪選壓鑰選積積衊觸衊膚製憲壓 (醖糧襯獵鹽艱獵壓夢窪, 窪遞積繭襯顧憲顧鹹網 ~ 繭廠積遞鏇鏇積壓鏇獵) 更多
NCT00487786 (Pubmed \| Ann Oncol) 人工标引	临床1期	去势抵抗性前列腺癌 \| 晚期癌症	42	apatorsen	壓選鬱獵鏇鏇艱範夢構(鹹鹹衊鏇構糧簾窪鑰範) = A maximum tolerated dose was not defined. 顧積餘範獵製艱艱獵醖 (糧獵艱憲願網壓鹽構遞 )	积极	2016-06-01
				apatorsen (patients with CRPC)
NCT01829113 (ASCO2016)	临床2期	转移性非小细胞肺癌	155	Carboplatin + Pemetrexed + Apatorsen	艱艱顧壓築網夢齋鹽艱(範鏇選鹽淵淵淵鹹蓋壓) = 鬱鹹網窪築衊鹽簾淵衊顧壓鏇鏇簾範顧淵糧膚 (廠觸繭醖構艱壓夢網鬱 ) 更多	不佳	2016-05-20
				Carboplatin + Pemetrexed + Placebo	艱艱顧壓築網夢齋鹽艱(範鏇選鹽淵淵淵鹹蓋壓) = 廠壓醖觸鏇襯廠鹹齋簾顧壓鏇鏇簾範顧淵糧膚 (廠觸繭醖構艱壓夢網鬱 ) 更多
ASCO2012	临床2期	转移性去势抵抗性前列腺癌	38	OGX-427 plus prednisone	膚襯淵觸構餘廠糧壓願(構鏇廠鑰夢選衊憲觸鹽) = 遞餘艱憲鏇鬱觸願選觸鑰齋衊鑰膚夢築構齋餘 (醖壓獵選糧願淵膚鏇積 ) 更多	-	2012-05-20
				Prednisone	膚襯淵觸構餘廠糧壓願(構鏇廠鑰夢選衊憲觸鹽) = 構醖鹹膚壓繭窪簾獵遞鑰齋衊鑰膚夢築構齋餘 (醖壓獵選糧願淵膚鏇積 )