NR1H2

NEW YORK, Dec. 20, 2023 (GLOBE NEWSWIRE) -- Anavex Life Sciences Corp. (“Anavex” or the “Company”) (Nasdaq: AVXL), a clinical-stage biopharmaceutical company developing differentiated therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders including Alzheimer’s disease, Parkinson’s disease, Rett syndrome and other central nervous system (CNS) diseases, today announced the first entire clinical gene pathway data from the ANAVEX®2-73-RS-002 AVATAR Rett syndrome trial. A whole genome and exome analysis comparing drug and placebo in patients with Rett syndrome was performed. We believe the results confirm that Rett syndrome is indeed a neurodevelopmental disorder with a key metabolic component, which can be addressed with therapeutic intervention and is likely relevant for other neurodevelopmental disease indications. AVATAR study was a randomized, placebo-controlled clinical trial in 33 patients with Rett syndrome which included prespecified biomarkers of response as well as Whole Exome Sequencing (WES) DNA data and full RNA exome expression (RNA-seq) data collection. The study included analysis of gene expression changes in each treatment group as well as analysis of the impact of single nucleotide polymorphisms/variants (SNPs/SNVs) on treatment response. ANAVEX®2-73 transcriptomics analysis (RNAseq) identified gene networks that are differentially expressed in Rett syndrome patients treated with ANAVEX®2-73 compared to placebo. Patient samples that were analyzed contained on average over 20 million unique reads in both placebo and ANAVEX®2-73 treated patients. Biological relevance of this pool of genes was assessed through pathway analysis and confirmed the impact of ANAVEX®2-73 treatment on pathways involved in neurodevelopmental diseases. The results highlight many significant differences between active treatment group and placebo, such as the differential expression of several genes in response to ANAVEX®2-73 treatment as shown in the following heatmap figure: Pathway analysis of the differentially expressed genes suggests ANAVEX®2-73 may, among other functions, correct metabolic alterations in patients with Rett syndrome through enhanced mitochondrial energy production and increased expression of genes involved in oxidative phosphorylation, fatty acid metabolism, developmental signaling pathways, transcription/translation, membrane trafficking, and branched-chain amino acid catabolism as shown in the following table: ANAVEX®2-73 Treatment-enriched Pathways Pathway Name Category p-value Oxidative phosphorylation Energy Metabolism 2.84E-04 Valine leucine and isoleucine degradation Metabolism 6.85E-04 Adipogenesis Energy Metabolism 1.48E-03 Fatty acid degradation Energy Metabolism 5.52E-03 Amino acid metabolism Metabolism 7.14E-03 Cysteine and methionine metabolism Metabolism 8.41E-03 Acyl chain remodeling of phosphatidylserine Metabolism 1.43E-02 Mitochondrial protein import Energy Metabolism 1.71E-02 α-Linolenic acid metabolism Metabolism 1.83E-02 PPAR-α pathway Signaling 1.98E-02 Acyl chain remodeling of phosphatidylethanolamine Metabolism 2.43E-02 TGF-β signaling pathway Signaling 2.49E-02 Deubiquitination Metabolism 2.99E-02 NOD1/2 signaling pathway Signaling 3.09E-02 Fatty acid β-oxidation Energy Metabolism 3.26E-02 Detoxification of reactive oxygen species Metabolism 3.26E-02 N-glycan trimming in ER and calnexin/calreticulin cycle Metabolism 3.44E-02 miRNAs involvement in the immune response in sepsis Transcription / Translation 3.81E-02 RHOV GTPase cycle Signaling 3.81E-02 Formation of xylulose-5-phosphate Metabolism 4.11E-02 NR1H2 and NR1H3 regulate gene expression linked to gluconeogenesis Transcription / Translation 4.11E-02 RHOU GTPase cycle Signaling 4.20E-02 Fatty acid metabolism Energy Metabolism 4.36E-02 Nucleotide-binding oligomerization domain (NOD) pathway Transcription / Translation 4.60E-02 Protein localization Membrane Trafficking 4.89E-02 Glycerophospholipid metabolism Metabolism 4.89E-02 The scope of these detected gene expression changes identified through ANAVEX®2-73 effect may represent additional potential biomarkers of disease pathology and response. Christopher U Missling, PhD, President and Chief Executive Officer of Anavex, stated, "We believe, this represents an extensive transcriptomics analysis (RNAseq) of a therapeutic agent in patients with Rett syndrome and it is very exciting to witness ANAVEX®2-73’s demonstration of its platform Precision Medicine potential for Rett syndrome with ability to compensate for expression levels of dysregulated developmental and metabolic genes, apparent within the Rett syndrome pathology. We are steadily making progress to learn more about this debilitating disorder and further analysis will be dedicated to evaluating the significance of each identified gene and gene variant and should deepen the understanding of the underlying signaling pathways involved in response to ANAVEX®2-73 treatment in patients with Rett syndrome.” About Anavex Life Sciences Corp. Anavex Life Sciences Corp. (Nasdaq: AVXL) is a publicly traded biopharmaceutical company dedicated to the development of novel therapeutics for the treatment of neurodegenerative and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, Rett syndrome, and other central nervous system (CNS) diseases, pain, and various types of cancer. Anavex's lead drug candidate, ANAVEX®2-73 (blarcamesine), has successfully completed a Phase 2a and a Phase 2b/3 clinical trial for Alzheimer's disease, a Phase 2 proof-of-concept study in Parkinson's disease dementia, and both a Phase 2 and a Phase 3 study in adult patients with Rett syndrome. ANAVEX®2-73 is an orally available drug candidate that restores cellular homeostasis by targeting sigma-1 and muscarinic receptors. Preclinical studies demonstrated its potential to halt and/or reverse the course of Alzheimer's disease. ANAVEX®2-73 also exhibited anticonvulsant, anti-amnesic, neuroprotective, and anti-depressant properties in animal models, indicating its potential to treat additional CNS disorders, including epilepsy. The Michael J. Fox Foundation for Parkinson's Research previously awarded Anavex a research grant, which fully funded a preclinical study to develop ANAVEX®2-73 for the treatment of Parkinson's disease. ANAVEX®3-71, which targets sigma-1 and M1 muscarinic receptors, is a promising clinical stage drug candidate demonstrating disease-modifying activity against the major hallmarks of Alzheimer's disease in transgenic (3xTg-AD) mice, including cognitive deficits, amyloid, and tau pathologies. In preclinical trials, ANAVEX®3-71 has shown beneficial effects on mitochondrial dysfunction and neuroinflammation. Further information is available at . You can also connect with the Company on Twitter,Facebook, Instagram, and LinkedIn. Forward-Looking Statements Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks set forth in the Company’s most recent Annual Report on Form 10-K filed with the SEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement and Anavex Life Sciences Corp. undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof. For Further Information: Anavex Life Sciences Corp. Research & Business Development Toll-free: 1-844-689-3939 Email: info@anavex.com Investors: Andrew J. Barwicki Investor Relations Tel: 516-662-9461 Email: andrew@barwicki.com A photo accompanying this announcement is available at . Heatmap Heatmap

我们的基因组DNA不断被内源性因素（如活性氧）和环境因素（如紫外线、辐射和化学物）所破坏。未能修复受损的DNA可能诱发突变和细胞死亡，最终导致癌症和其他疾病的发生。为了防止这种情况，我们的细胞配备了多 我们的基因组DNA不断被内源性因素（如活性氧）和环境因素（如紫外线、辐射和化学物）所破坏。未能修复受损的DNA可能诱发突变和细胞死亡，最终导致癌症和其他疾病的发生。为了防止这种情况，我们的细胞配备了多种防御系统，旨在寻找和修复受损的DNA。 核苷酸切除修复（nucleotide excision repair, NER）是一种修复由紫外线和化学致癌物引起的各种DNA损伤的重要机制。许多被诊断为着色性干皮病（xeroderma pigmentosum, XP）的患者在编码参与NER机制的蛋白的基因之一中存在突变。众所周知，这些患者对紫外线引起的皮肤癌的高易感性是由于NER功能的缺乏。这也告诉我们，NER是对癌症的一种防御。 NER的第一步涉及XPC蛋白，它是多种XP致病性基因产物之一，它作为一种“传感蛋白”起作用，用于确定DNA结构中的异常所在的位置。XPC有潜力处理各种各样的DNA损伤，同时它也能结合到没有任何损伤的DNA位点，比如碱基错配。由于在这种不适当的位点进行不必要的修复反应可能会增加不良突变的风险，因此必须验证是否有任何必须修复的损伤。尽管以前已证实基础转录因子TFIIH和XPA蛋白在这样的损伤验证步骤中发挥了作用，但到目前为止，这种详细机制仍不清楚。 根据NER过程中已知的反应步骤，来自美国国家糖尿病、消化及肾病研究所以及日本神户大学等研究机构的研究人员在一项新的研究中制备了一系列含有受损DNA的依次由XPC、TFIIH和XPA结合的复合物，然后通过低温电镜详细分析了它们的分子结构。相关研究结果近期发表在Nature期刊上，论文标题为“Lesion recognition by XPC, TFIIH and XPA in DNA excision repair”。 TFIIH是一种由七个亚基（包括XPB和XPD蛋白）组成的大型蛋白复合物，它在NER和转录（基因表达）中都起着关键作用。它通常采用U形的“马蹄形”结构，XPB和XPD蛋白位于它的两个开放臂的顶端。 这种马蹄形结构在DNA-XPC-TFIIH复合物中得到了保留，XPB在损伤位点与XPC结合，而XPD既不与DNA相互作用，也不与XPC相互作用。然而，当XPA随后参与进来时，TFIIH经历了一个重大的构象变化。当这种马蹄形结构的两个开放臂聚集在一起形成一种环形结构时，XPB远离了损伤位点，这样XPD就可以在两者之间结合DNA。 那么这种分子排列如何验证DNA损伤的存在呢？众所周知，XPB作为一种“DNA转位酶”发挥功能，它与DNA双链结合并沿着其中一条DNA链移动。根据这种新阐明的复合物结构，有理由认为XPB应该沿着DNA移动，远离损伤位点。然而，由于它受到其他蛋白的限制，XPB本身实际上不能移动。相反，DNA双链向相反的方向移动。换句话说，XPB将DNA推入这种复合物。 NER复合物的结构。图片来自Nature, 2023, doi:10.1038/s41586-023-05959-z。 鉴于这种结构显示XPA的一部分被插入在XPB后面的两条DNA链之间，因此预计它将像解开紧固件一样将DNA双链解开为单链。此外，还已知XPD与单链DNA结合，并沿一种规定的方向（5'→3'）移动。 在被XPB和XPA解开的两条DNA链中，XPD与受损的DNA链结合。然而，与XPB的情况一样，XPD本身不能移动，所以受损的DNA链也同样被拉向这种复合物。当与单链DNA结合时，在XPD中形成一个狭窄的针孔，DNA链通过该针孔。因此，如果DNA链上存在较大的损伤，该部分将被困于XPD的入口处，从而使该链停止移动（就像一根打结的线无法通过针眼一样）。 因此，这项新的研究成功地阐明了验证DNA损伤存在的机制：通过XPD阻断DNA链的移动来决定是否继续进行修复反应。事实上，以前的研究已表明，可以预测通过XPD针孔的非大体积的DNA损伤（碱基脱落等）并不是NER修复过程的目标。 这项新的研究明确了XPA、XPB和XPD等蛋白的哪些部分参与了修复受损DNA的NER过程，以及它们的作用机制。随着我们对XP患者中这些蛋白的致病变体所引起的结构变化对修复反应的负面影响的了解加深，也有可能在未来支持药物和其他治疗方法的开发。（生物谷 Bioon.com） 参考资料： 1. Jinseok Kim et al. Lesion recognition by XPC, TFIIH and XPA in DNA excision repair. Nature, 2023, doi:10.1038/s41586-023-05959-z. 2. New insight into how xeroderma pigmentosum causative gene products ensure the accuracy of DNA repairhttps://phys.org/news/2023-06-insight-xeroderma-pigmentosum-causative-gene.html

New data supports the future development of LP-100 in combination with PARP inhibitors for earlier lines of treatment including metastatic prostate cancer and other indications where PARP inhibitors are being utilized. Synergistic potency was observed for LP-100 in combination with multiple PARP inhibitors and supported with in-silico analysis from billions of data points and real world patient data sets from RADR® - Lantern’s AI platform for drug development. Lantern is exploring development of a new clinical trial in cancers with mutations in DDR (DNA Damage Response) genes such as BRCA1/2 and ATM, which will build upon the results from LP-100’s prior Phase 2 trial conducted in Denmark in metastatic castration-resistant prostate cancer (mCRPC). In the Phase 2 clinical trial in Denmark, the median overall survival (OS) for the initial group of 9 patients was approximately 12.5 months, which is an improvement over other similar fourth-line treatment regimens for mCRPC. Lantern estimates that the future development of LP-100 in combination with PARP inhibitors may increase the annual potential market size of LP-100 targeted indications to between $700 million and $2 billion, while also positioning the drug candidate in multiple genomically defined DDR cancers that align with its mechanism of action. DALLAS--(BUSINESS WIRE)-- Lantern Pharma, Inc. (NASDAQ: LTRN), a clinical-stage biopharmaceutical company using its proprietary RADR® artificial intelligence ("AI") and machine learning (“ML”) platform to transform the cost, pace, and timeline of oncology drug discovery and development, today announced new data for its product candidate LP-100 supporting the development of LP-100 in combination with the class of anticancer agents known as PARP inhibitors (PARPi). In prostate cancer mouse xenograft studies, LP-100 demonstrated synergistic potency when used in combination with the FDA-approved PARP inhibitor Olaparib. LP-100 also demonstrated synergy with the FDA-approved PARP inhibitors Olaparib, Rucaparib, and Niraparib in ovarian cancer cell line studies. The observations from these studies are further supported by in-silico evaluation of LP-100 in combination with PARP inhibitors using Lantern’s AI platform, RADR®. “The combined anti-tumor potency of LP-100 in combination with PARP inhibitors, strongly supports the pursuit of this development pathway for LP-100,” stated Panna Sharma, Lantern’s President and CEO. “We also believe this development focus will enhance the potential to position LP-100 in earlier lines of therapy, while also opening the door to pursue treatment indications with larger market sizes,” continued Sharma. “Exposure to LP-100 results in double-strand DNA breaks and PARP inhibitors prevent the repair of these types of breaks. We believe this mechanistic combination provides a potent and highly synergistic method to eradicate tumors.” LP-100 and PARP inhibitors act by complementary mechanisms. LP-100 acts by a synthetically lethal mechanism of action that preferentially damages DNA in cancer cells lacking nucleotide excision repair (NER) capabilities. Sensitivity to LP-100 is also higher in tumors with homologous recombination repair (HRR) deficiency, suggesting that this pathway is also involved in the repair of DNA damage from LP-100. PARP inhibitors have been shown to be effective in the treatment of tumors with HRR deficiencies. Lantern believes the simultaneous exploitation of both these mechanisms will enhance the development opportunities for LP-100, while also expanding potential market opportunities for existing PARP inhibitors. LP-100 has previously been in a genomic signature guided Phase 2 clinical trial in Denmark where the drug candidate was used without PARP inhibitors for patients with metastatic castration-resistant prostate cancer (mCRPC). In this trial 9 patients (out of a targeted enrollment of 27) were treated and had a median overall survival (OS) of approximately 12.5 months, which is an improvement over other similar fourth-line treatment regimens for mCRPC. “Based on these results, the synergies of LP-100 with PARPi, along with the increasingly narrow field of patients in mCRPC due to the emergence of radio-ligand based therapies, we believe that the positioning of LP-100 in an earlier and more genomically defined setting is the best use of our resources and can lead to improved patient outcomes,” continued Sharma. In conjunction with its evaluation work on LP-100 with PARP inhibitors, Lantern has been collaborating with the Danish Cancer Society Research Center (DCSRC) to explore the future clinical potential of LP-100 across 9 different solid tumor types that have known deficiencies in DNA repair pathway mechanisms. This work has included an examination of the role of NER deficiency in breast, ovarian, prostate, lung, kidney, bladder, stomach, pancreatic, and esophageal cancers, with the aim of identifying the most promising patient populations for future LP-100 therapy. Lantern expects to present additional details on the results of its collaboration with DCSRC later this year. Based on Lantern’s evaluation of the synergies of LP-100 with PARP inhibitors, and the industry’s development of entirely new classes of radio-ligand based therapy for mCRPC, the decision has been made to close the Phase 2 clinical trial in Denmark, to allow the focus of LP-100-directed resources on positioning the molecule for development in earlier lines of therapy with potentially larger market opportunities. Earlier line treatment indications where Lantern believes LP-100 in combination with PARPi could have potential future treatment benefits include prostate cancer indications such as HRR gene-mutated metastatic castration-resistant prostate cancer, ovarian cancer indications such as first line platinum-responsive advanced ovarian cancer, and breast cancer indications such as germline BRCA-mutated metastatic breast cancer. The total U.S. market size of these and other potential target development indications for the LP-100 and PARPi combination is estimated at between $700 million and $2 billion. About Lantern Pharma: Lantern Pharma (NASDAQ: LTRN) is a clinical-stage oncology-focused biopharmaceutical company leveraging its proprietary RADR® AI and machine learning platform to discover biomarker signatures that identify patients most likely to respond to its pipeline of genomically-targeted therapeutics. By targeting drugs to patients whose genomic pro them as having the highest probability of benefiting from the drug, Lantern's approach represents the potential to deliver best-in-class outcomes. Forward-looking Statements: This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. These forward-looking statements include, among other things, statements relating to: future events or our future financial performance; the potential advantages of our RADR® platform in identifying drug candidates and patient populations that are likely to respond to a drug candidate; our strategic plans to advance the development of our drug candidates and antibody drug conjugate (ADC) development program; estimates regarding the development timing for our drug candidates and ADC development program; expectations and estimates regarding clinical trial timing and patient enrollment; our research and development efforts of our internal drug discovery programs and the utilization of our RADR® platform to streamline the drug development process; our intention to leverage artificial intelligence, machine learning and genomic data to streamline and transform the pace, risk and cost of oncology drug discovery and development and to identify patient populations that would likely respond to a drug candidate; estimates regarding patient populations, potential markets and potential market sizes; sales estimates for our drug candidates and our plans to discover and develop drug candidates and to maximize their commercial potential by advancing such drug candidates ourselves or in collaboration with others. Any statements that are not statements of historical fact (including, without limitation, statements that use words such as "anticipate," "believe," "contemplate," "could," "estimate," "expect," "intend," "seek," "may," "might," "plan," "potential," "predict," "project," "target," "model," "objective," "aim," "upcoming," "should," "will," "would," or the negative of these words or other similar expressions) should be considered forward-looking statements. There are a number of important factors that could cause our actual results to differ materially from those indicated by the forward-looking statements, such as (i) the impact of the COVID-19 pandemic, (ii) the risk that our research and the research of our collaborators may not be successful, (iii) the risk that none of our product candidates has received FDA marketing approval, and we may not be able to successfully initiate, conduct, or conclude clinical testing for or obtain marketing approval for our product candidates, (iv) the risk that no drug product based on our proprietary RADR® A I platform has received FDA marketing approval or otherwise been incorporated into a commercial product, and (v) those other factors set forth in the Risk Factors section in our Annual Report on Form 10-K for the year ended December 31, 2021, filed with the Securities and Exchange Commission on March 10, 2022. You may access our Annual Report on Form 10-K for the year ended December 31, 2021 under the investor SEC filings tab of our website at or on the SEC's website at . Given these risks and uncertainties, we can give no assurances that our forward-looking statements will prove to be accurate, or that any other results or events projected or contemplated by our forward-looking statements will in fact occur, and we caution investors not to place undue reliance on these statements. All forward-looking statements in this press release represent our judgment as of the date hereof, and, except as otherwise required by law, we disclaim any obligation to update any forward-looking statements to conform the statement to actual results or changes in our expectations.