A Phase 1b, Open Label, Dose Escalation Study of IOA-289, an Orally Bioavailable, Selective Autotaxin (ENPP2) Inhibitor Alone and in Combination With Gemcitabine/Nab-paclitaxel in Patients With Metastatic Pancreatic Cancer

The objective of study IOA-289-102 is to evaluate the safety and tolerability of escalating doses of IOA-289 in patients with metastatic pancreatic cancer in combination with standard chemotherapy consisting of gemcitabine and nab-paclitaxel. Blood and tumour samples for PK and PD will be collected and assessments for determination of any clinical efficacy will be completed.

开始日期2022-10-10

申办/合作机构

iOnctura SA初创企业

NCT05027568 / Recruiting临床1期

Randomized, Double-blind, Placebo-controlled, Dose Escalation Study for the Assessment of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Ascending Oral Doses of IOA-289 in Healthy Male Volunteers

The purpose of Part 1 of this First-in-Human trial is to evaluate the safety and tolerability after single ascending oral doses of IOA-289 given to healthy male subjects, compared to placebo. After the oral dose administrations, the amount of IOA-289 present in serum will be determined for pharmacokinetic characterisation. Also the reduction of LPA in plasma will be determined as a pharmacodynamic biomarker.
Part 2 is optional and its conduct will be dependent on the pharmacokinetic data generated in Part 1. Part 2 will be a randomized, crossover, open label, single oral dose administration of IOA-289 to healthy male subjects either in a fasted state, or after a high-fat meal.

开始日期2021-07-05

申办/合作机构

iOnctura SA初创企业

100 项与 Cambritaxestat 相关的临床结果

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100 项与 Cambritaxestat 相关的转化医学

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100 项与 Cambritaxestat 相关的专利（医药）

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项与 Cambritaxestat 相关的文献（医药）

2023-06-01·Immuno-oncology technology

Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors

Article

作者: Niewola-Staszkowska, K ; Pergher, M ; Mikulčić, N ; Johnson, Z ; Di Conza, G ; Shah, P ; Ziviani, L ; Pickering, C ; van der Veen, L ; Peyruchaud, O ; Deken, M A ; Lahn, M ; Tagliavini, A ; Nizzardo, A ; Milleri, S ; Antolić, M ; Cheasty, A

Background:

Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile.

Materials and methods:

In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose.

Results:

In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA.

Conclusions:

Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.

2023-05-26·Cancers

Autotaxin Inhibition with IOA-289 Decreases Breast Tumor Growth in Mice Whereas Knockout of Autotaxin in Adipocytes Does Not.

Article

作者: Brindley, David N ; Deken, Marcel A ; Tang, Xiaoyun ; Morris, Andrew J

Breast cancer cells produce negligible quantities of autotaxin. Instead, previous work indicated that adipocytes in the inflamed adipose tissue adjacent to breast tumors are a major source of autotaxin secretion that drives breast tumor growth, metastasis, and the loss of efficacy for chemotherapy and radiotherapy. To test this hypothesis, we used mice with an adipocyte-specific knock out of autotaxin. The lack of autotaxin secretion from adipocytes failed to decrease the growth of orthotopic E0771 breast tumors in syngeneic C57BL/6 mice and the growth and lung metastasis of spontaneous breast tumors in MMTV-PyMT mice. However, the inhibition of autotaxin with IOA-289 decreased the growth of E0771 tumors, indicating that another source of autotaxin is responsible for tumor growth. Tumor-associated fibroblasts and leukocytes produce the majority of autotoxin transcripts in the E0771 breast tumors, and we hypothesize that they are the main sources of ATX that drive breast tumor growth. Autotaxin inhibition with IOA-289 increased the numbers of CD8α⁺-T-cells in the tumors. This was accompanied by decreases in the concentrations of CXCL10, CCL2, and CXCL9 in the plasma and LIF, TGFβ1, TGFβ2, and prolactin in the tumors. Bioinformatics analysis of human breast tumor databases showed that autotaxin (ENPP2) is expressed mainly in endothelial cells and fibroblasts. Autotaxin expression correlated significantly with increases in IL-6 cytokine receptor ligand interactions, signaling by LIF, TGFβ, and prolactin. This confirms the relevance of results from autotaxin inhibition in the mouse model. We propose that inhibiting autotaxin activity that is derived from cells presenting breast tumors such as fibroblasts, leukocytes, or endothelial cells changes the tumor micro-environment in such a way as to inhibit tumor growth.

2022-08-01·Journal of pharmaceutical and biomedical analysis

Validation of an LC–MS/MS method for the quantification IOA-289 in human plasma and its application in a first-in-human clinical trial

Article

作者: Mameli, M ; Calusi, G ; van der Veen, L ; Breda, M ; Lahn, M ; Greco, A ; Vezzelli, A ; Cardin, R ; Johnson, Z ; Franchi, J ; Deken, M A

IOA-289 is a novel small molecule inhibitor of autotaxin developed as a first-in-class therapy of fibrotic pathologies including cancer. A method for quantitation of IOA-289 in human plasma was developed using a stable isotope labeled compound ([¹³C₄]IOA-289) as internal standard. The analytes were extracted from human plasma by protein precipitation and the analysis was performed by liquid chromatography coupled with tandem mass spectrometric detection (LCMS/MS). The chromatographic separation was performed with a gradient elution from a BEH C18 column and under these conditions the retention time and the run time were 1 and 2 min, respectively. The assay was fully validated over the range 3-3000 ng/mL, proved to be accurate, precise and selective and was successfully applied to quantitate IOA-289 in plasma samples from subjects in a first-in-humanclinical trial.

项与 Cambritaxestat 相关的新闻（医药）

2024-07-09

·PRNewswire

iOnctura announces expansion of roginolisib clinical trial program to NSCLC

Phase II study in non-small-cell-lung-cancer (NSCLC) to be run in collaboration with the ETOP IBCSG Partners Foundation across sites in Europe Study will investigate dostarlimab + roginolisib +/- docetaxel in patients with NSCLC resistant to first-line checkpoint inhibitor therapy GENEVA and AMSTERDAM, July 9, 2024 /PRNewswire/ -- iOnctura, a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers, today announces expansion of the clinical trial program for lead pipeline asset, roginolisib. Via clinical collaboration agreements with the ETOP IBCSG Partners Foundation and GSK, roginolisib will be evaluated in combination with dostarlimab in NSCLC. Roginolisib is an allosteric modulator of PI3Kδ, widely recognized as a 'master switch' of cancer. Inhibition of PI3Kδ unleashes a multi-pronged anti-tumor and immune response to combat the tumor1 . Roginolisib has demonstrated an unprecedented clinical profile in solid and liquid cancers2, with 44 patients treated to date. Emerging clinical and translational biomarker data supports the hypothesis that combining roginolisib with a programmed death receptor-1 (PD-1) targeting agent, with or without docetaxel, may prevent or reverse drug resistance in NSCLC and may show synergistic anti-tumor immune activity without significant addition of toxicity3. Dostarlimab is a PD-1-blocking antibody approved for certain patients with endometrial cancer, which has also demonstrated clinical activity in combination with chemotherapy in NSCLC4. Under the terms of the agreement with iOnctura, GSK will supply dostarlimab for use in a randomized Phase II clinical trial in NSCLC patients resistant to first-line checkpoint inhibitor therapy, with or without docetaxel. iOnctura will retain worldwide rights to roginolisib. The ETOP IBCSG Partners Foundation is a leading organization performing international clinical and translational research in thoracic malignancies and breast cancer. Through the clinical collaboration, iOnctura will be provided access to a network of highly experienced investigators for the Phase II study. Professor Solange Peters, MD, PhD, Chair of Medical Oncology and the Thoracic Malignancies Programme in the Department of Oncology at the University Hospital of Lausanne will be the primary coordinating investigator of the study. Catherine Pickering, Chief Executive Officer of iOnctura, said: "As iOnctura moves into the next phase of clinical development, we are thrilled to be able to assess the effectiveness of roginolisib in combination with dostarlimab for the treatment of NSCLC. The successful uveal melanoma data reported so far, combined with a rich preclinical data package, support the rationale to expand our development program with potentially synergistic combinations in NSCLC." Solange Peters, Professor and Chair of Medical Oncology & Thoracic Malignancies Programme in the Department of Oncology at the University Hospital of Lausanne in Lausanne, Switzerland, commented: "On behalf of the ETOP IBCSG Partners Foundation, we are intrigued by the benefit/risk profile of roginolisib. In patients who no longer respond to current therapies, we wish to investigate whether roginolisib in combination with dostarlimab provides a novel treatment option. ETOP IBCSG Partners Foundation is committed to investigate novel treatment options to help our patients." About iOnctura iOnctura is a clinical-stage biopharmaceutical company combating neglected and hard-to-treat cancers with precision oral small molecules that target cancers in novel ways. The bold new treatments extend lives and improve healthspans, changing the outlook for patients and their families. Two therapeutic candidates have progressed into mid-stage clinical development: roginolisib is the first allosteric modulator of PI3Kδ and cambritaxestat is the only autotaxin inhibitor in clinical development to treat cancer. iOnctura BV is headquartered in Amsterdam, The Netherlands with its wholly owned Swiss subsidiary, iOnctura SA, located in Geneva, Switzerland. iOnctura is backed by specialist institutional investors including Syncona, EIC Fund, M Ventures, Inkef Capital, VI Partners and Schroders Capital. About roginolisib Roginolisib is the first allosteric modulator of PI3Kδ with a unique chemical structure and binding mode. The PI3K signalling pathway is one of the most commonly dysregulated pathways in cancer and the precise targeting of the PI3Kδ isoform delivers substantial anti-tumor effects with a low-toxicity profile. Clinical data have demonstrated roginolisib's excellent safety profile and sustained clinical activity in uveal melanoma (UM), a rare eye cancer with few available treatments. Randomized Phase II trials are planned to start in late 2024 in UM and other cancers, including non-small cell lung cancer and primary myelofibrosis. About the ETOP IBCSG Partners Foundation The ETOP IBCSG Partners Foundation was established through the merger of the European Thoracic Oncology Platform (ETOP) and the International Breast Cancer Study Group (IBCSG) (ETOP IBCSG Partners Foundation). The foundation, with its legal seat in Bern, Switzerland, has become a leading organization in performing international clinical research in thoracic malignancies and breast cancer. The ETOP IBCSG Partners Foundation is sponsoring and managing an increasing number of clinical trials and translational research projects in Europe and beyond. 1 AACR Volume 3, Issue 4, April 2023, Poster presentation, SITC 2022 2 Poster presentation, ESMO-IO 2023 3 Poster presentation, ESMO-IO 2023, Poster presentation EACR 2023 4 Lim, S.M. et al., Nat Commun 14, 7301 (2023) SOURCE iOnctura

临床2期引进/卖出

2024-07-09

·Pharmaceutical Technology

iOnctura expands PI3K inhibitor programme to NSCLC

The expansion to roginolisib’s clinical programme is via collaborations with ETOP IBCSG Partners Foundation and GSK. Image credit: Shutterstock/tomertu. Fresh from raising nearly $86m in financing last month, iOnctura will now start evaluating lead asset roginolisib in non-small cell lung cancer (NSCLC). The expansion to roginolisib’s clinical programme is via clinical collaboration agreements with the ETOP IBCSG Partners Foundation and GSK , iOnctura said in a 9 July press release. The Swiss biopharma iOnctura outlined plans for a Phase II study that will investigate roginolisib in combination with GSK’s PD-1 inhibitor Jemperli (dostarlimab). The combo therapy will be evaluated in NSCLC patients resistant to first-line checkpoint inhibitor therapy, with or without docetaxel. Roginolisib is an allosteric modulator of phosphoinositide 3-kinase-δ (PI3Kδ), which iOnctura says is “widely recognised as a ‘master switch’ of cancer.” Inhibition of the protein elicits an anti-tumour effect, which induces immune system activity against cancer cells. In January this year, roginolisib received an orphan drug designation from the US Food and Drug Administration (FDA). iOnctura is basing the combination with GSK’s programmed death receptor (PD-1) on “emerging clinical and translational biomarker data,” adding that it may prevent or reverse drug resistance in NSCLC. This enhanced anti-tumour immune activity would also be without significant addition of toxicity, according to the biopharma. See Also: Dupixent “addresses current gap” in COPD biologics landscape Peltopepimut-s by ISA Pharmaceuticals for Cervical Cancer: Likelihood of Approval Roginolisib is being evaluated in a Phase I clinical trial (NCT04328844) as a monotherapy and in combination with chemotherapy in patients with advanced or metastatic cancers, including metastatic uveal melanoma . The biopharma reported positive efficacy results at the 80mg dose, with grade 1 and 2 adverse events observed in the continuous daily dosing portion of the trial for patients with solid tumors. iOnctura’s CEO Catherine Pickering said: “The successful uveal melanoma data reported so far, combined with a rich preclinical data package, support the rationale to expand our development program with potentially synergistic combinations in NSCLC.” P13K inhibitors faced a setback in recent years after the FDA’s Oncologic Drugs Advisory Committee (ODAC ) lost confidence in the safety profile of the drugs. The agency recommended that future approvals of PI3K inhibitors for haematologic malignancy indications should require randomised trial data, as per a vote in 2022. The decision was based on high levels of fatal adverse events (AEs) and toxicity observed in patients taking the drug class. Roche made a recent advancement in the space, securing FDA priority review in breast cancer for the PI3K inhibitor inavolisib as a combination therapy with fulvestrant and Pfizer ’s Ibrance (palbociclib). iOnctura raised €80m ($85.8m) in Series B financing earlier this year, helping to fund Phase II activity for roginolisib and its other candidate cambritaxestat, autotaxin inhibitor.

临床1期临床结果孤儿药优先审批临床2期

2024-06-21

·药明康德

预防糖尿病的安全口服疗法；创新细胞疗法获FDA优先审评资格……

▎药明康德内容团队编辑预防糖尿病，口服疗法达到2期临床主要终点 Aphaia Pharma公司日前宣布，其用于治疗糖尿病前期的在研疗法APHD-012在2期临床试验中达到了主要终点。数据显示，与安慰剂相比，APHD-012在6周给药后在口服葡萄糖耐受测试（OGTT）异常的个体中显著改善了葡萄糖耐受，并且具有良好的安全性。在一组包含健康人、糖尿病前期和糖尿病患者的志愿者中，6周APHD-0126治疗在OGTT中将血糖水平从9.0±0.6 mmol/L降低到7.9±0.6 mmol/L（n=23，p=0.01）；接受安慰剂治疗无显著效果（从8.8±0.4 mmol/L降至8.5±0.6 mmol/L；p=0.33）。亚组分析显示，APHD-012在糖尿病前期患者中的效果更显著，将血糖水平从8.7±0.4 mmol/L降低到6.8±0.5 mmol/L；n=12，p=0.003）；在该亚组中，安慰剂无显著效果。 APHD-012是一种专有的口服葡萄糖配方，设计在小肠的特定部位释放，以恢复内源性营养感知信号通路，并刺激控制多种稳态功能的广谱肠激素的释放，包括胰高血糖素样肽1（GLP-1）、胰多糖素和氧促胰多糖素（OXM）等。创新细胞疗法获FDA优先审评资格，治疗视网膜退化疾病 Neurotech Pharmaceuticals公司日前宣布，为细胞疗法revakinagene taroretcel（NT-501）递交的生物制品许可申请（BLA）获得FDA授予的优先审评资格，用于治疗2型黄斑毛细血管扩张症（MacTel）。 Revakinagene taroretcel基于该公司独特的封装细胞疗法（encapsulated cell therapy，ECT）平台。它将表达睫状神经营养因子（CNTF）的同种异体视网膜色素上皮（RPE）细胞封装在微小的移植物中，这些移植物在植入到眼睛中后可以持续释放CNTF，从而延缓视网膜退化，潜在改善患者的长期视力。移植物具有通透性的外膜在允许营养物质进入和CNTF释放的同时，保护移植细胞不受到宿主免疫系统的攻击，确保它们的长期存活和功能。 Revakinagene taroretcel在两项3期临床试验中已经获得积极结果，显著降低了2型MacTel患者的疾病进展速度。亨廷顿病疗法2期临床结果积极 PTC Therapeutics日前分享了在研疗法PTC518治疗亨廷顿病（HD）患者的2期临床试验PIVOT-HD的中期结果。在第12个月时，接受PTC518治疗患者队列中显示出剂量依赖性突变亨廷顿蛋白（mHTT）的降低。此外，多项与HD相关的临床评估都表现出有利趋势。而且经过12个月的治疗，PTC518继续表现良好的安全性和耐受性。数据显示，在第12个月时，5 mg和10 mg剂量的PTC518分别将血液中的mHTT水平降低了22%和43%。在脑脊液中，5 mg和 10 mg剂量分别降低mHTT水平21%和43%。此外，在第12个月时，PTC518在缓解运动症状进展上表现出显著效果，根据总运动评分（TMS）评估，5 mg和10 mg剂量组的症状加重分别为2.0和1.3分，而安慰剂组为4.9分。开发潜在“first-in-class”PI3Kδ别构调节剂，新锐完成8000万欧元融资 iOnctura日前宣布完成8000万欧元的B轮融资。iOnctur正在开发一系列精准口服小分子抗癌药物。该公司已将两种候选疗法推进到中期临床开发阶段。主打在研药物roginolisib是一款PI3Kδ别构调节剂，具有独特的化学结构和结合模式。新闻稿指出，roginolisib有潜力成为首个成功靶向PI3Kδ关键癌症通路的治疗方法。此次融资将用于加速roginolisib用于治疗葡萄膜黑色素瘤（UM）的临床试验，这是一种眼部罕见癌症，目前可用的治疗方法很少。在一项1b期临床试验中，roginolisib在UM中表现出长期安全性和可喜的疗效，且在数月内持续保持临床活性。 iOnctura的第二个临床开发项目cambritaxestat是一款autotaxin抑制剂，用于治疗autotaxin过表达的高度纤维化肿瘤。目前，cambritaxestat联合化疗治疗转移性胰腺癌的1b期临床试验正在进行中。 2.75亿美元合作！潜在“best-in-class”疗法即将进入临床 Alivexis和Melodia Therapeutics今日宣布，双方已签署了一项独家许可协议，在全球范围内开发、制造和商业化Alivexis的MDI-0151，这是一种具有“best-in-class”潜力的组织蛋白酶C（cathepsin C）抑制剂。Melodia将迅速启动MDI-0151的IND申请，为针对多种由中性粒细胞过度激活引起的难治性炎症性疾病的1/2a期临床试验做准备。根据协议条款，Alivexis授予Melodia在全球范围内开发、制造和商业化MDI-0151的权利，并将从Melodia获得高达约2.75亿美元的预付款和开发及销售里程碑付款。MDI-0151抑制的组织蛋白酶C是一种负责激活在中性粒细胞破坏组织中起重要作用的蛋白酶的酶。由于抑制组织蛋白酶C对中性粒细胞的免疫功能影响较小，MDI-0151可能在有效治疗各种免疫和炎症性疾病同时，不会削弱免疫系统。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] Neurotech Receives Priority Review of Biologics License Application (BLA) for NT-501 (revakinagene taroretcel) as a Treatment for Macular Telangiectasia Type 2 (MacTel). Retrieved June 20, 2024, from https://www.neurotechpharmaceuticals.com/receives-priority-review-for-bla-for-nt-501/ [2] iOnctura announces EUR80 million Series B financing to progress pipeline through Phase II trials. Retrieved June 20, 2024, from https://wp-ionctura-2024.s3.eu-west-2.amazonaws.com/media/2024/06/iOnctura-Financing-PR-19-6-FINAL.pdf [3] Interim PIVOT-HD Results Demonstrate Evidence of Favorable CNS Biomarker and Clinical Effects at Month 12 in Huntington's Disease Patients. Retrieved June 20, 2024, from https://ir.ptcbio.com/news-releases/news-release-details/interim-pivot-hd-results-demonstrate-evidence-favorable-cns [4] APHAIA PHARMA ANNOUNCES POSITIVE RESULTS FROM PHASE 2 TRIAL EVALUATING ITS LEAD DRUG FORMULATION. Retrieved June 20, 2024, from https://aphaiapharma.com/news/aphaia-pharma-announces-positive-results-from-phase-2-trial-evaluating-its-lead-drug-formulation/ [5] Melodia Therapeutics and Alivexis Sign Exclusive License Agreement for Cathepsin C Inhibitor Program MOD-A. Retrieved June 21, 2024, from https://www.businesswire.com/news/home/20240620110656/en/Melodia-Therapeutics-and-Alivexis-Sign-Exclusive-License-Agreement-for-Cathepsin-C-Inhibitor-Program-MOD-A 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

优先审批临床2期细胞疗法临床结果ASH会议

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适应症	最高研发状态	国家/地区	公司	日期
胰腺癌	临床2期	意大利	iOnctura SA初创企业	2022-10-10
胰腺癌	临床2期	英国	iOnctura SA初创企业	2022-10-10
胰腺导管腺癌	临床1期	英国	iOnctura SA初创企业	-
胃癌	临床1期	英国	iOnctura SA初创企业	-

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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


NCT05586516 (ASCO2024) 人工标引	临床1/2期	转移性胰腺导管腺癌	13	IOA-289 (100 mg + Cohort 1)	糧壓夢鏇淵餘選製壓鏇(獵顧壓築顧願簾憲衊觸) = None 齋網壓選醖糧繭鏇獵築 (鹽鹹顧夢衊鬱廠鏇獵膚 ) 更多	积极	2024-05-24
NCT05586516 (ASCO2024) 人工标引	临床1/2期	转移性胰腺导管腺癌	13	IOA-289 (200 mg + Cohort 2)	糧壓夢鏇淵餘選製壓鏇(獵顧壓築顧願簾憲衊觸) = None 齋網壓選醖糧繭鏇獵築 (鹽鹹顧夢衊鬱廠鏇獵膚 ) 更多	积极	2024-05-24
ATS2021	N/A	肺纤维化	-	IOA-289	遞膚繭鹹繭淵糧醖廠艱(製選構顧廠獵鏇鏇選網) = 遞齋築壓鏇衊淵蓋蓋鹹鹹廠餘膚繭獵鹹淵範糧 (製膚餘蓋築構簾選醖淵 )	-	2021-05-03