ARG1

Initiation of Phase II clinical trial of OATD-01 (KITE) for the treatment of pulmonary sarcoidosis following approval from the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). World's first administration of a chitotriosidase 1 inhibitor (or placebo) to a patient with active pulmonary sarcoidosis as part of the Phase II OATD-01 clinical trial (proof-of-concept in human) at a hospital in the UK. First success in mRNA platform development - inhibited translation of pathogenic proteins in a cellular assay (in vitro proof-of-concept) - achieving an important discovery milestone in the development of a breakthrough small-molecule drug platform targeting mRNA. Further advances in the Phase I clinical trial of OATD-02, the first-in-class dual arginase inhibitor being developed for the treatment of cancer, systematic dose escalation and progression to a fourth cohort of patients with solid tumours, to determine the maximum tolerated dose and recommended dose for the next phase of trials. Further development of the most advanced project in the preclinical phase - the USP7 inhibitor programme for use in anti-cancer therapies using artificial intelligence tools and models. Warsaw, April 3, 2024. - Molecure S.A. ("Molecure", WSE ticker: MOC), a biotechnology company that discovers and develops drugs to the clinical stage and leverages its globally unique expertise in medicinal chemistry and biology to explore and develop first-in-class small-molecule drugs that directly modulate protein activity and mRNA function to treat a range of incurable diseases, has published its 2023 annual report. The report is available at: “2023 was an exceptional year for Molecure as we made significant progress in the development of both clinical and preclinical programmes, particularly in the area of small-molecule drugs targeting mRNA. We initiated clinical trials of our drug candidate, which was discovered and brought into clinical trials for cancer patients by Molecure. We have made significant progress with OATD-02, a dual arginase inhibitor, and will soon begin administering the drug (at a dose of 20 mg) to a fourth cohort of patients with solid tumors. We are also seeing an increase in biomarkers suggesting a pharmacodynamic effect in the absence of significant side effects. In 2023, our focus was also on preparing for a Phase II clinical trial for OATD 01, Molecure's flagship clinical programme. We obtained FDA and then MHRA approval to initiate a Phase II clinical trial of OATD-01 in patients with pulmonary sarcoidosis. It is noteworthy that we went through the whole procedure very smoothly, which demonstrates the high quality of our research and documentation. We are very pleased to report that the first patient has started dosing in a clinical trial at a clinical site in the UK. OATD-01 is a first-in-class chitinase inhibitor developed by Molecure scientists for the treatment of sarcoidosis, which will be administered to placebo-controlled patients. We are shortly awaiting Phase II clinical trial approvals for OATD-01 from regulatory authorities in Denmark, France, Greece, Germany and Norway. Last year was also a time to continue Molecure's transformation into a cutting-edge company, applying the latest generative and predictive artificial intelligence techniques to our early drug discovery programmes, including a platform of small-molecule drugs interacting directly with mRNA targets. We achieved our first major success with Proof-of-Concept in vitro, confirming the inhibition of protein translation with compounds targeting the mRNA encoding the protein. We also adopted an approach to identifying the most promising preclinical projects, aiming to maintain a balanced portfolio of projects with strong clinical and transactional potential. The last two years have been difficult for biotech companies due to the destabilisation of the geopolitical environment, inflation and interest rates, which slowed down partnership discussions and capital raising. Despite these difficulties, thanks to investors' faith in the potential of our programmes, we successfully completed a capital round and raised approximately PLN 50 million in growth funding from investors through a share issue. Our clinical development is incurring increasing costs, but we have our own funding and awarded grants that will allow us to continue with both clinical projects and those with the best earlier stage of development until at least early 2025. In parallel, we are applying for new grants to support projects and IT and computational methods, which will allow us to accelerate the development of programmes. We are confident that pursuing our mission will open up new treatment opportunities for patients and provide a significant return on investment for shareholders. We thank you for your trust to date and encourage you to continue working with us.” - said Marcin Szumowski, CEO of Molecure S.A. Presentation for investors The Company's presentation to investors will take place on 10th April 2024, at 2 pm (CEST) in an online meeting format, under the link: Selected key developments in 2023 and up to the date of publication of the financial report Strategy Update The Company's main strategic objectives in the area of R&D and business development are: Continued intensive clinical development of two key projects: completion of a Phase II study for OATD-01 in sarcoidosis and completion of a Phase I clinical trial for OATD-02 in oncology patients, with possible expansion to additional indications and combination therapies Further development of early preclinical stage projects, including the identification of 1-2 advanced lead compounds (candidates for preclinical development) and the introduction of a further programme to the clinical trial stage Accelerate the development of a breakthrough platform of small-molecule drugs targeting mRNA, including the achievement of in vitro PoC and the selection of lead molecules Increasing the efficiency of drug discovery processes (by reducing time and cost and lowering the risk of failure) through investment in machine learning and generative artificial intelligence (GenAI) technology Conclusion of at least 1 high-value partnership agreement for at least one clinical-stage project, as well as the establishment of a number of commercial collaborations, including profit-sharing, for earlier-stage programmes Investment expenditures, among others, for the implementation of the objectives set out in the Strategy in the period from 2024 to the end of 2025 have been set at approximately PLN 150 million. Successful completion of a public offering (SPO) Molecure has successfully raised gross proceeds of approximately PLN 50m from its public share offering from existing and new shareholders The funds raised from the SPO and expected grants will be used to fund the Company's growth plans and continue to build a balanced portfolio of breakthrough therapies including first-in-class drugs, including the completion of a Phase II study of OATD-01 in sarcoidosis and the completion of a Phase I clinical trial of OATD-02 in oncology patients, with the potential to expand into additional indications and combination therapies Phase II clinical trial approvals for OATD-01 and initiation of the trial Molecure has received approval from the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) to conduct a Phase II clinical trial for OATD-01 in the US and UK. The proof-of-concept Phase II study is the first to administer the drug to patients with pulmonary sarcoidosis. The world's first patient administration of chitotriosidase inhibitor 1 (CHIT1) or placebo took place in March this year at the Royal Infirmary in Edinburgh. As part of the trial, patients will take a fixed dose of 25 mg OATD-01 or placebo daily in tablet form for 12 weeks Molecure has reapplied for permission to conduct a Phase II clinical trial of OATD-01 in EU countries: Denmark, France, Greece, Germany and Norway. In the previous coordinated assessment procedure, a refusal decision was issued by the Polish Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, and the effect of the refusal was that, despite receiving approval from the ethics committees in Greece, Germany, France, Denmark, Poland and Norway, it was not possible to conduct the clinical trial in the requested EU countries, as Poland was reported in the application as the rapporteur country. In the re-proceeding, Molecure proposed Denmark as a rapporteur country in the application assessment process. Phase I clinical trial OATD-02 Achieving significant progress in the clinical development of OATD-02, an oral, potent and selective first-in-class arginase (ARG1 and ARG2) inhibitor, in cancer therapies March 2023 saw the administration of OATD-02 to the first oncology patient in a Phase I clinical trial to evaluate the safety, tolerability and preliminary efficacy of OATD-02 in patients with advanced and/or metastatic solid tumors Continued systematic dose escalation and planned imminent commencement of administration in a fourth cohort of patients with solid tumors, to determine the maximum tolerated dose and recommended dose for the next phase of the study Development of the mRNA platform Molecure confirms the efficacy of small molecules in inhibiting the translation of pathogenic proteins achieving a key milestone in the development of a breakthrough platform of small-molecule drugs targeting mRNAs In vitro proof-of-concept (PoC) assay confirms inhibition of protein translation with compounds targeting the mRNA encoding the protein The PoC stage for the first molecule developed in the mRNA platform provides evidence of the effectiveness of Molecure's strategy to identify mRNA-binding compounds with therapeutic potential The success achieved in the development of the mRNA platform increases the likelihood of signing a collaboration agreement with partners working in this area Receipt of funding for a project to develop small-molecule drugs directly interacting with mRNA under the SMART pathway of the FENG programme (European Funds for a Modern Economy). The amount of funding is approximately PLN 32.5 million with a total project budget of approximately PLN 51.5 million. The project will be implemented between 2023 and 2028 Business Development In 2023, Molecure representatives held a total of 107 meetings with biotech industry representatives in Europe and the US (Basel, London, Boston, Munich), mainly with potential partners, investors and global pharmaceutical companies. OATD-01 (37 meetings), OATD-02 (25 meetings) and USP7 (23 meetings) attracted the most interest. As a result of the meetings held, the Company signed 11 non-disclosure agreements (CDAs) with interested companies. This year, representatives of the Company were present at the BIO-Europe conference in Barcelona, which took place from 18-20 March Key organisational changes in 2023 relevant to the growth and advancement of research programme Appointment of Dr Samson Fung - Chief Medical Officer to the Company's Board of Directors to support the clinical development of OATD-01 and OATD-02 Dr Zbigniew Zasłona has been promoted to Chief Scientific Officer from his previous role as VP Research Biology. Dr Zasłona remains a member of the Board of Directors of Molecure Summary of financial data in 2023 Operating income of PLN 1.3 million, up from PLN 1.6 million in 2022. Operating expenses were PLN 23.4 million, up PLN 4.8 million from 2022, due to the progressive advancement of the Company's programmes and pipeline expansion. Increase mainly due to an increase in salaries and wages, increasing early-stage research costs and third-party service costs Net loss in 2023 amounted to PLN 18.3 million compared to a net loss of PLN 15.3 million in the same period in 2022 As at 31 December 2023, Molecure had cash and cash equivalents of nearly PLN 64 million. As at the date of publication of the Annual Report (29 March 2024), the Company has approximately PLN 54 million at its disposal - the Company has a stable capital position necessary to continue to finance the Company's dynamic growth. In addition, contracted grant funding for the coming years amounts to PLN 32.5 million. The Company plans to obtain further grants for projects within the framework of the pipeline developed so far. *** About Molecure S.A. Molecure S.A. is a biotechnology company that discovers and develops drugs to the clinical stage, using its own unique expertise in medicinal chemistry and biology to search for and develop first-in-class small-molecule drugs that, through direct modulation of previously unexplored protein and RNA targets, could provide therapies for many incurable diseases. Molecure has generated a diverse portfolio of seven distinct programmes with the support of leading academic research institutions around the world, including Yale University, Rutgers University, the Flemish Institute for Biotechnology (VIB) in Ghent, the University of Michigan and the International Institute of Molecular and Cell Biology in Warsaw (MIBMiK). The most advanced drug candidate developed by Molecure is OATD-01, a first-in-class CHIT1 inhibitor for the treatment of interstitial lung diseases such as sarcoidosis and idiopathic pulmonary fibrosis, which is ready to enter Phase II clinical trials. The Phase II study in sarcoidosis patients started in Q4 2023 in the US and the UK and will also continue in the EU and Norway, after gaining the appropriate regulatory approval. The second drug candidate is OATD-02, an oral, selective, first-in-class, dual arginase inhibitor (ARG1 and ARG2) for the treatment of cancer, whose Phase I clinical trial has begun with first patient administration in Q1 2023. Molecure's headquarters and laboratories are located in Warsaw and Lodz. The company is listed on the Warsaw Stock Exchange (ticker: MOC). Detailed information can be found on: LinkedIn: Molecure | Twitter: @molecure_sa | YouTube: Molecure SA

本文为转化医学网原创，转载请注明出处 作者：Jerry 导读： 研究表明，CCR7作为一种重要的炎症因子，可促进口腔鳞状细胞癌(oral squamous cell carcinoma, OSCC)的增殖和转移，但其在肿瘤微环境(tumor microenvironment, TME)中的作用尚不明确。 3月27日，中国医科大学刘法昱研究团队在期刊《JouRNAl of Experimental & Clinical Cancer Research》发表了研究论文，题为“Analysis of the effect of CCR7 on the microenvironment of mouse oral squamous cell carcinoma by single-cell RNA sequencing technology”。本研究中，研究人员构建了CCR7基因敲除小鼠和OSCC小鼠模型，并通过单细胞RNA测序(scRNA-seq)和生物信息学来分析3只CCR7基因敲除小鼠(KO)和3只野生型小鼠(WT)之间OSCC微环境的差异。使用免疫组化、免疫荧光染色和流式细胞术来分析KO和WT组之间显著不同的细胞类型中关键基因的表达。另外，还进行了体外实验来验证CCR7对M2巨噬细胞极化的影响。 研究结果表明，CCR7可促进M2型巨噬细胞极化，从而促进口腔鳞癌细胞的增殖、侵袭和迁移。 https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03013-y#Sec16 研究背景 01 口腔癌是全球第六大常见恶性肿瘤。超过90%的口腔癌起源于口腔鳞状上皮组织，这种类型的癌症被广泛称为口腔鳞状细胞癌(OSCC)。目前，主要的治疗方案包括手术切除、化疗和放疗，这些治疗方法增加了患者的发病率。尽管这些传统治疗方法取得了进展，但口腔鳞状细胞癌患者的五年生存率仍低于70%。近年来，免疫治疗受到了极大的关注，并在多种恶性肿瘤中取得了良好的效果。尽管抗PD-1/PD-L1抗体已被美国食品药品监督管理局(FDA)批准用于治疗OSCC，但总体缓解率仍然较低。因此，寻找针对OSCC的特异性免疫治疗靶点对患者管理变得越来越重要。 研究方法 02 研究人员分析了KO组和WT组因OSCC微环境变化导致的肿瘤生长差异。然后，对WT组(B2、B9、B47)和KO组(B30、B76、B77)的肿瘤进行scRNA-seq。初步质控后共获得70316个细胞。然后，使用Doublet Finder R包排除多细胞的干扰，将无多细胞干扰的58,836个细胞用于后续分析。Seurat R软件包进行数据简化和细胞簇可视化分析，t-SNE软件共显示25个细胞簇。Single R初步的细胞簇可以与部分免疫细胞相匹配，但不能区分成纤维细胞和肿瘤细胞。然后根据报道使用inferCNV R包区分良恶性细胞。最终鉴定出8个簇(1、2、5、6、8、12、14、17)为恶性细胞。另外17个细胞簇被鉴定为良性细胞，然后得到最终的聚类注释结果(见图1h)。 图1：CCR7对小鼠口腔鳞状细胞癌微环境的影响——单细胞RNA测序技术分析 体外实验中，研究人员将THP-1细胞用PMA诱导为M0型巨噬细胞，再用IL-4 + IL-13诱导为M2型巨噬细胞，实时荧光定量PCR结果显示M2组中M2标志物CD206、ARG-1、IL-10和TGF-β的表达水平高于M0组，表明诱导成功。加入CCR7 mAb后诱导作用明显受到抑制，表明CCR7可阻断M2极化。PCI-4B和PCI-37B细胞与M2型巨噬细胞共培养后，细胞迁移和侵袭能力明显增强，而用CCR7 mAb预处理M2型巨噬细胞后，肿瘤细胞(PCI-4B、PCI-37B)的迁移和侵袭能力明显降低。 在划痕实验和CCK-8实验中也观察到类似结果，表明CCR7诱导的M2极化可促进肿瘤细胞的存活、迁移和侵袭。 为了研究CCR7的作用机制,研究人员根据SCRA-SEQ的结果,还比较了不同细胞之间的基因变化。 研究结论 03 以上结果表明，CCR7基因敲除可显著抑制OSCC的肿瘤生长并影响肿瘤的TME, ScRNA-seq和体外实验结果表明CCR7可能通过抑制Dusp1的表达促进M2型巨噬细胞极化，从而促进OSCC的增殖和转移。 参考资料： https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03013-y#Sec16 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

OATD-01 is an innovative, first-in-class chitinase inhibitor for the treatment of sarcoidosis among other diseases where chronic inflammation leads to tissue remodeling and fibrosis In the phase II clinical trial (KITE study), patients will take a daily oral dose of 25 mg OATD-01 or placebo (in tablet form) for 12 weeks The double-blind, randomised, placebo-controlled study is designed to determine the clinical efficacy, pharmacokinetics, pharmacodynamics and safety of OATD-01 The Phase II study will be conducted in the UK, US, and the European Union including Norway, and will involve approximately 100 patients OATD-01 is a first-in-class chitotriosidase 1 (CHIT1) inhibitor with disease-modifying potential in sarcoidosis and other interstitial lung diseases Warsaw, March 22, 2024. - Molecure S.A. ("Molecure", WSE ticker: MOC), a biotechnology company that discovers and develops drugs to the clinical stage and uses its globally unique expertise in medicinal chemistry and biology to explore and develop first-in-class small-molecule drugs that directly modulate protein activity and mRNA translation to treat a range of incurable diseases, has started the clinical trial where OATD-01 is being administered to patients with active pulmonary sarcoidosis as part of a Phase II clinical trial (proof-of-concept in human). The world's first administration of the chitotriosidase 1 (CHIT1) inhibitor (or placebo) to patient took place at the Royal Infirmary in Edinburgh. As part of the trial, patients will take a daily fixed dose of 25 mg OATD-01 or placebo tablets for 12 weeks. Patient safety will be monitored regularly through laboratory tests, neurological examinations and ECG and spirometry. The Phase II clinical trial for OATD-01 is designed as a randomised, double-blind, placebo-controlled, multi-center study to evaluate the safety and efficacy of the oral CHIT1 inhibitor (OATD-01) in approximately 100 patients with active pulmonary sarcoidosis, including patients both previously receiving other therapies and previously untreated. The study will involve approximately 20-30 centres in the US, the European Union, Norway and the UK. The renowned CRO (Contract Research Organisation) Simbec Orion is responsible for the organization and comprehensive conduct of the study. „The first administration to a patient with pulmonary sarcoidosis is the realization of our mission focused on helping and transforming the lives of patients with incurable diseases through the development of therapies and the opportunity to offer them new treatment options. Launched in the UK, the Phase II trial involving patients with active disease, the 'proof-of-concept in human' phase, is a significant milestone in the clinical development of our lead program. It is a landmark moment also because it is the first time that a chitotriosidase 1 inhibitor has been offered to patients. Molecure is a pioneer and global leader in the development of therapies based on the inhibition of chitinase activity. The 'PoC in human' study is key to validating this therapeutic approach, as there is a whole spectrum of diseases whose development is associated with similar molecular mechanisms. We will conduct the study in the United States, the United Kingdom, Norway and European Union countries, after obtaining approvals from the relevant EU regulators. The results of this study will be strategically important for further value creation and commercialization of OATD-01, and we look forward to the results of the study in 2025" - said Dr Marcin Szumowski, Chief Executive Officer and Chairman of the Management Board of Molecure S.A. Due to the double-blinding requirement of the study, publication of the final unblinded results will follow completion of the study and is anticipated by the end of 2025. For the efficacy trial, an innovative primary endpoint has been agreed with the FDA, namely the response to 12-week administration of OATD-01 as measured by the degree of reduction in granulomatous inflammation in the lung parenchyma, as assessed by PET/CT imaging. After approximately 50 patients have completed their participation in the study, a sub-analysis (intermediate checkpoint) will be scheduled to statistically evaluate the results by an independent committee and decide how to proceed with the study in terms of the number of patients. „We are very proud of the first patient administration in the KITE study. In a broad spectrum of preclinical studies, we have confirmed the great potential of OATD-01 to become the new standard of care for pulmonary sarcoidosis. In phase 1 clinical trials involving 129 healthy volunteers, we in turn confirmed the good safety pro OATD-01 and the compound's ability to effectively block chitinases. In a phase 2 study, we aim to demonstrate that blocking chitinases in patients has a therapeutic effect and inhibits inflammatory processes. The primary endpoint of the study is the arrest or reversal of disease progression and lung damage as assessed by the granulomatous inflammation reduction score. The therapy also aims to alleviate the symptoms of the disease understood as an improvement in lung function, as measured by a change in the so-called Forced Vital Capacity (FVC), as well as an improvement in quality of life and a shift away from corticosteroids’’ - said Dr Samson Fung, Chief Medical Officer and Board Member of Molecure S.A. About OATD-01 OATD-01 is an orally administered once-daily, first-in-class and highly selective CHIT1 inhibitor for potential use in the treatment of sarcoidosis. The CHIT1 enzyme represents a promising molecular target due to its role in converting local anti-inflammatory macrophages into pro-inflammatory and pro-fibrotic types. Blocking CHIT1 activity by OATD-01 resulted in documented anti-inflammatory and anti-fibrotic effects. The OATD-01 molecule has demonstrated potent anti-inflammatory and anti-fibrotic effects in various disease models and has high therapeutic potential in a variety of inflammatory and fibrotic diseases representing an unmet medical need, such as sarcoidosis, as well as idiopathic pulmonary fibrosis (IPF) and non-alcoholic steatohepatitis (NASH). Molecure has obtained orphan drug designation (ODD) from the FDA for OATD-01 in the indications of sarcoidosis and idiopathic pulmonary fibrosis. About sarcoidosis Sarcoidosis is a multi-organ disease of unknown etiology, characterized by the formation of granulomatous structures in various organs, mainly the lungs and lymphatic system. Sarcoidosis is a globally prevalent disease, affecting both men and women with an incidence estimated at 5-50 cases per 100,000 population, with 70% of patients being between 25-45 years of age. The most serious and common complication of sarcoidosis is pulmonary fibrosis. It is usually associated with significant impairment of lung function. Pulmonary fibrosis accounts for the majority of sarcoidosis-related deaths in Western countries. About Molecure S.A. Molecure S.A. is a biotechnology company that discovers and develops drugs to the clinical stage, leveraging its own unique expertise in medicinal chemistry and biology to search for and develop first-in-class small-molecule drugs that, through direct modulation of previously unexplored protein and RNA targets, may provide therapies for many incurable diseases. Molecure has generated a diverse portfolio of seven distinct programmes with support from leading academic research institutions around the world, including Yale University, Rutgers University, the Flemish Institute for Biotechnology (VIB) in Ghent, the University of Michigan and the International Institute of Molecular and Cell Biology in Warsaw, Poland (MIBMiK). The most advanced drug candidate developed by Molecure is OATD-01, a first-in-class CHIT1 inhibitor for the treatment of interstitial lung diseases such as sarcoidosis and idiopathic pulmonary fibrosis, which is ready to enter Phase 2 clinical trials. The phase 2 trial in sarcoidosis patients started in Q4 2023 in the US and the UK and will also continue in the EU and Norway, after gaining the appropriate regulatory approval. The second drug candidate is OATD-02, an oral, selective, first-in-class, dual arginase inhibitor (ARG1 and ARG2) for the treatment of cancer, whose Phase I clinical trial has started with first patient administration in Q1 2023. Molecure's headquarters and laboratories are located in Warsaw and Lodz. The company is listed on the Warsaw Stock Exchange (ticker: MOC). Detailed information can be found at: LinkedIn: Molecure | Twitter: @molecure_sa | YouTube: Molecure SA