Investigation of effectiveness of sake yeast supplementation (Saccharomyces cerevisiae) and S-sdenosyl methionine (SAM) in pharmacoresistant epileptic patients

Start Date03 Apr 2022

Sponsor / Collaborator

Semnan University

NCT03887169 / CompletedPhase 1/2IIT

Oral or Enteral Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.

The purpose of this study is to determine the safety and tolerance of an oral administration of methionine in the treatment of pulmonary alveolar proteinosis due to the double mutation Ala393Thr / Ser567Leu in the MARS gene. This disease is very severe and especially leads to chronic respiratory insufficiency. There is no curative treatment for this disease. The MARS gene encodes the methionine tRNA synthetase (MetRS). Mutations in this gene leads to a defect in MetRS function. In cultured mutated yeast, addition of methionine in culture medium restores MetRS function. Therefore, the investigators hypothesized that treatment of patients with methionine could have beneficial effects on the disease.

Start Date16 Sep 2019

Sponsor / Collaborator

Assistance Publique des Hôpitaux de Paris SA

100 Clinical Results associated with Methionine

100 Translational Medicine associated with Methionine

100 Patents (Medical) associated with Methionine

18,139

Literatures (Medical) associated with Methionine

01 Feb 2025·Food Chemistry

Insight into the oxidation mechanism of coconut globulin by atmospheric cold plasma focusing on side chain amino acids

Article

Author: Zhang, Weimin ; Li, Tong ; Luo, Yangchao ; Li, Tian ; Chen, Yang

Atmospheric cold plasma (ACP), a novel non-thermal processing technology, generates active substances that stimulate protein oxidation in protein-based foods. Nevertheless, the precise mechanism through which ACP initiates amino acid oxidation on protein side chains remains ambiguous. This study primarily aimed to elucidate the mechanism of ACP-induced oxidation of coconut globulin, focusing on the process of amino acid oxidation. Analysis of protein oxidation products indicated a positive correlation between the extent of protein oxidation and the voltage and duration of ACP treatment. By analyzing the composition of amino acids and active ingredients, the study identified that the most significant changes amino acids were methionine, cysteine, and arginine, and •OH was the primary free radicals. The findings from oxidation kinetics and dynamic simulation indicated that •OH predominantly oxidized methionine, followed by L-cysteine and L-arginine. These results offer theoretical framework for understanding protein oxidation by ACP and suggest potential applications in protein-based food.

01 Jan 2025·Metabolism

Hepatocyte-specific SLC27A4 deletion ameliorates nonalcoholic fatty liver disease in mice via suppression of phosphatidylcholine-mediated PXR activation

Article

Author: Zhao, Jian ; Zhong, Yanhua ; Gao, Yong ; Gonzalez, Frank J ; Liu, Min ; Zhao, Ling ; Zhong, Chong ; Wang, Wei ; Gonzalez, Frank J. ; Shen, Chuangpeng ; Miao, Deyu ; Pan, Zhisen ; Xie, Wenmin ; Liu, Changhui

BACKGROUNDThe protein Solute carrier family 27 member 4 (SLC27A4) is crucial for fatty acid synthesis and β-oxidation, but its role in hepatic steatosis and nonalcoholic fatty liver disease (NAFLD) progression is not fully understood.METHODSMice with AAV-mediated overexpression of Slc27a4 in liver and hepatocytes-specific deletion of Slc27a4 were fed a standard chow diet, a high-fat diet (HFD), or a methionine and choline-deficient diet (MCD). Serum and liver tissues were collected and analyzed by biochemical assay, histology, lipidomic analysis, RNA-seq analysis, qPCR, western blot and immunofluorescence.RESULTSThis study found elevated expression of SLC27A4 in individuals with NAFLD and OAPA-treated MPHs cells, leading to increased lipid accumulation and diet-induced liver steatosis, inflammation, and fibrosis. Conversely, hepatocyte-specific deletion of Slc27a4 improved the development of both NAFLD and NASH. SLC27A4 overexpression resulted in increased hepatic pregnane X receptor (PXR) expression and accumulation of phosphatidylcholine (PC), which activates PXR signaling and inducing SLC27A4 expression. PXR overexpression hinders the protective impact of Slc27a4 deletion on lipid accumulation and inflammation, whereas its deficiency in mice reduces the effect of Slc27a4 overexpression on NAFLD development.CONCLUSIONThese results indicate that SLC27A4 plays a critical role of lipid accumulation and inflammation, and is implicated in the development of NAFLD progression, rendering it potentially actionable target for NAFLD treatment.

01 Jan 2025·Talanta

An intelligent sensing platform for detecting and identifying biochemical substances based on terahertz spectra

Article

Author: Wu, Meizhang ; Cao, Yunhao ; Huang, Xiwen ; Chen, Yusa ; Wu, Wengang ; Zhao, Guozhong ; Xiong, Shisong ; Meng, Tianhua ; Sun, Hongshun ; Ma, Lijun ; Li, Liye

This paper presents the development of an intelligent sensing platform dedicated to accurately identifying terahertz (THz) spectra obtained from various biochemical substances. The platform currently has two distinct identification modes, which focus on identifying five amino acids, namely phenylalanine, methionine, lysine, leucine, and threonine, and five carbohydrates, namely aspartame, fructose, glucose, lactose monohydrate, and sucrose based on their THz spectra. The first mode, called One-dimensional THz Spectrum Identification (OTSI), combines THz time-domain spectroscopy (THz-TDS) with the proposed mini convolutional neural network (MCNN) model. THz-TDS detects biochemical substances, while the MCNN model identifies the THz spectra. The MCNN model has a simple structure and only needs to deal with the THz absorption coefficients of biochemical substances, which are less computationally intensive and easily converged. The model can achieve 99.07 % accuracy in identifying one-dimensional THz spectra of the ten biochemical substances. The second mode, THz Spectrum Image-based Identification (TSII), applies the YOLO-v5 target detection model to THz spectral image recognition. The YOLO-v5 model uses THz absorption peaks as identification features and can identify biochemical substances based on only one or several THz absorption peaks. The overall identifying accuracy of the YOLO-v5 model for ten biochemical substances is 96.20 %. We also compared the MCNN and YOLO-v5 models with other deep learning and machine learning models, which demonstrate that they have better performance. This feature broadens the platform's utility in biomolecular analysis and paves the way for further research and development in detecting and analyzing diverse biological compounds.

News (Medical) associated with Methionine

19 Jul 2023

·www.sciencedaily.com

More than just lifestyle and genes: New factor influencing excess body weight discovered

What determines whether we become overweight? Aside from lifestyle, predisposition plays a role, but genes cannot fully explain the inherited propensity to accumulate excess weight. A new study shows that a kind of formatting of the DNA code in one gene that is associated with satiety is implicated in a slightly elevated risk of excess body weight -- at least in women. This 'epigenetic marking' is established early on during the embryonic stage. What determines whether we become overweight? Aside from lifestyle, predisposition plays a role, but genes cannot fully explain the inherited propensity to accumulate excess weight. A new study by Charité -- Universitätsmedizin Berlin in Science Translational Medicine* shows that a kind of formatting of the DNA code in one gene that is associated with satiety is implicated in a slightly elevated risk of excess body weight -- at least in women. This "epigenetic marking" is established early on during the embryonic stage. People who are overweight, especially those who are severely overweight, are at increased risk of a number of serious diseases such as cardiovascular disease, diabetes, and cancer. It is a growing health issue. All over the world, the number of overweight people is increasing. In the European Region, two out of three adults (59 percent) are overweight or obese, according to the World Health Organization. But what determines whether people will become overweight? Genetic predisposition plays a major role, alongside lifestyle. The similarity of the body mass index (BMI) in identical twins ranges from 40 to 70 percent. Even identical twins raised in different families still show the same significant similarity. Scientists have identified several genetic variants that influence a person's body weight -- and with it, the risk of developing obesity. But even taken all together, they cannot explain the heritability that has been observed. Researchers began to suspect there must be additional non-genetic factors that affect a person's propensity to gain excess weight. Satiety gene is not altered, but formatted Researchers led by Prof. Peter Kühnen, Director of the Department of Pediatric Endocrinology at Charité, have now identified one such factor in their recent study. According to their findings, women's risk of being overweight increases by about 44 percent if there are an especially large number of methyl groups adhering to the POMC (pro-opiomelanocortin) gene, which is responsible for the feeling of satiety. Methyl groups are tiny chemical units the body uses to mark the letters in the DNA code to activate or deactivate genes without modifying the sequence of letters in the DNA. In other words, the effect is much like highlighting a section of a text without rewriting the text itself. This type of "DNA formatting" is known as epigenetic marking. For their study, the team of researchers analyzed the "formatting" of the POMC gene in more than 1,100 people. They found more methyl groups attached to the satiety gene in obese women with a BMI of over 35 than in women with normal body weight. "A 44 percent increase in the risk of obesity is about the same as the effect that has been observed for individual gene variants as well," says Kühnen. "By comparison, socioeconomic factors have a much stronger effect. They can increase the risk by a factor of two to three. As for why the methylation effect only shows up in women, we don't know yet." The POMC gene is "formatted" very early on during embryonic development, as the researchers showed by comparing methylation patterns in more than 15 sets each of identical and fraternal twins. While the "formatting" of the satiety gene was the same in most of the identical twins, there was hardly any correlation in the fraternal twins. "This indicates that the epigenetic marking of the POMC gene is established shortly after the egg and sperm cells merge, before the fertilized egg divides into two twin embryos," explains Lara Lechner, the study's first author, who works at the Department of Pediatric Endocrinology. This means the very early stage of pregnancy is crucial. What influences formatting? But what influences how much methylation the satiety gene undergoes -- and thus, the risk that a person will become overweight? Past studies indicated that the presence or absence of certain nutrients that supply methyl groups could have an effect on epigenetic processes. These nutrients include betaine, methionine, and folic acid, all of which are typically absorbed through a person's diet. A newly developed method involving individual human stem cells allowed the Charité researchers to simulate in the lab how the methylation pattern is determined during embryonic development and how nutrients affect it. "On the one hand, our studies and others as well show that folic acid, betaine, and other nutrients have a limited effect on the extent of methylation," Kühnen notes. "We've observed that the 'DNA formatting system' is very stable on the whole, with cells compensating for minor fluctuations in the nutrient supply. On the other hand, there are indications that the variability of this 'formatting' develops at random. That means that it is not possible -- not yet, at any rate -- to externally influence whether a person has more or less methylation in the POMC region." Medications may help At least in theory, women who are at elevated risk of developing obesity due to methylation of the POMC gene could receive medications to help them lose weight, as initial studies of four severely obese women and one man with this exact type of "formatting" of the satiety gene suggest. The subjects were given a specific drug that curbs the feeling of hunger and has already been approved to treat obese patients with a mutation of the POMC gene. Within three months after starting treatment, all five patients experienced less hunger. They lost an average of seven kilograms, or about five percent of their body weight. Some of them continued the treatment and continued to lose weight. "These findings show, for a start, that a POMC gene that has undergone epigenetic changes can in fact potentially be addressed through medication," Kühnen says. "Further large controlled studies will be needed to show whether treatment with this drug would also be effective over a longer period, and if so, how effective and how safe this type of treatment is. Overall, though, a medication like this would still need to be just one piece of a holistic treatment strategy."

Drug ApprovalClinical ResultOligonucleotide

04 Jun 2023

·www.businesswire.com

TAGRISSO® achieved unprecedented survival in early-stage EGFR-mutated lung cancer, with 88% of patients alive at five years in ADAURA Phase III trial

WILMINGTON, Del.--( BUSINESS WIRE )--Positive results from the ADAURA Phase III trial showed AstraZeneca’s TAGRISSO ® (osimertinib) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS), compared to placebo in the adjuvant treatment of patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection with curative intent. These results will be presented today in an oral presentation during the Plenary Session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA3). TAGRISSO reduced the risk of death by 51% compared to placebo in both the primary analysis population (Stages II-IIIA) (21% data maturity, OS hazard ratio [HR] of 0.49; 95.03% confidence interval [CI] 0.33-0.73; p=0.0004), and in the overall trial population (Stages IB-IIIA) (18% data maturity, OS HR of 0.49; 95.03% CI 0.34-0.70; p<0.0001). In the primary analysis population, an estimated 85% of patients treated with TAGRISSO were alive at five years compared to 73% on placebo. In the overall trial population, an estimated 88% of patients treated with TAGRISSO were alive at five years compared to 78% on placebo. Median OS was not yet reached in either population or treatment group. Patients on placebo that recurred with metastatic disease had the opportunity to receive TAGRISSO as a subsequent treatment. Roy S. Herbst, MD, PhD, Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, New Haven, Connecticut, US, and principal investigator in the trial, said: “ These highly anticipated overall survival results, with 88 per cent of patients alive at five years, are a momentous achievement in the treatment of early-stage EGFR-mutated lung cancer. These data underscore that adjuvant treatment with osimertinib provides patients with the best chance of long-term survival.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “ TAGRISSO cut the risk of death by more than half in the adjuvant setting, further establishing this transformative medicine as the backbone treatment for EGFR-mutated lung cancer. These results emphasize the importance of diagnosing patients with lung cancer early, testing for EGFR mutations and treating all those with an EGFR mutation with TAGRISSO.” Summary of OS results: ADAURA i TAGRISSO Placebo Stages II-IIIA (primary population) (n=233) (n=237) Median OS (in months) Not reached Not reached Hazard ratio (95.03% CI) 0.49 (0.33-0.73) p-value 0.0004 OS rate (%) (five years) (95% CI) 85 (79-89) 73 (66-78) Stage IB-IIIA (overall population) (n=339) (n=343) Median OS (in months) Not reached Not reached Hazard ratio (95.03% CI) 0.49 (0.34-0.70) p-value <0.0001 OS rate (%) (five years) (95% CI) 88 (83-91) 78 (73-82) i The data cut-off date was 27 January, 2023. At the previously reported disease-free survival analysis, all patients had completed or discontinued treatment. The safety and tolerability of TAGRISSO with extended follow-up were consistent with its established profile and previous analyses with no new safety concerns reported. Adverse events at Grade 3 or higher from all causes occurred in 23% of patients in the TAGRISSO arm versus 14% in the placebo arm. IMPORTANT SAFETY INFORMATION There are no contraindications for TAGRISSO Interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of the 1479 TAGRISSO-treated patients; 0.3% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed Heart rate-corrected QT (QTc) interval prolongation occurs in TAGRISSO-treated patients. Of the 1479 TAGRISSO-treated patients in clinical trials, 0.8% were found to have a QTc >500 msec, and 3.1% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Cardiomyopathy occurred in 3% of the 1479 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 3.2% of 1233 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of TAGRISSO-treated patients experienced LVEF decreases ≥10% from baseline and a drop to <50%. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO Keratitis was reported in 0.7% of 1479 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if SJS or EMM is suspected and permanently discontinue if confirmed Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.07% of 1479) and postmarketing. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO. Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose Most common (≥20%) adverse reactions, including laboratory abnormalities, were leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough INDICATIONS TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy Please see complete Prescribing Information , including Patient Information for TAGRISSO. You may report side effects related to AstraZeneca products by clicking here . Notes Lung cancer Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths. 1 Lung cancer is broadly split into NSCLC and small cell lung cancer. 2 The majority of all NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis. 4‑5 Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition. 7‑8 For patients with resectable tumors, the majority eventually develop recurrence despite complete tumor resection and adjuvant chemotherapy. 9 ADAURA ADAURA was a randomized, double-blind, placebo-controlled, global Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II, IIIA EGFRm NSCLC following complete tumor resection and, at physicians’ and patients’ discretion, adjuvant chemotherapy. Patients were treated with TAGRISSO 80mg once-daily oral tablets or placebo for three years or until disease recurrence. The trial was enrolled in more than 200 centers across more than 20 countries, including the US, Europe, South America, Asia and the Middle East. The primary endpoint was DFS in Stage II and IIIA patients and key secondary endpoints included DFS in Stage IB, II and IIIA patients, and OS in both the primary and overall populations. Though the primary data readout was originally anticipated in 2022, data from the trial were reported early following a recommendation from an Independent Data Monitoring Committee (IDMC) based on its determination of overwhelming efficacy. TAGRISSO ® TAGRISSO ® (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system metastases. TAGRISSO (40mg and 80mg once-daily oral tablets) has been used to treat nearly 700,000 patients across its indications worldwide and AstraZeneca continues to explore TAGRISSO as a treatment for patients across multiple stages of EGFRm NSCLC. In addition to investigating TAGRISSO in early-stage disease, AstraZeneca is also studying the medicine in combination with chemotherapy in locally advanced and metastatic EGFRm NSCLC (FLAURA2). The Company is also researching ways to address tumor mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test TAGRISSO given concomitantly with savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company's comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including tremelimumab-actl and gefitinib; durvalumab and tremelimumab-actl; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; savolitinib in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines in Oncology, Rare Diseases and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow us on Twitter @AstraZenecaUS . References World Health Organisation. International Agency for Research on Cancer. Lung Fact Sheet. Available at https://gco.iarc.fr/today/data/factsheets/cancers/15-Lung-fact-sheet.pdf . Accessed March 2023. LUNGevity Foundation. Types of Lung Cancer. Available at https://lungevity.org/for-patients-caregivers/lung-cancer-101/types-of-lung-cancer . Accessed March 2023. Cheema PK, et al. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol. 2019;26(1):37-42. Cagle P, et al. Lung Cancer Biomarkers: Present Status and Future Developments. Archives Pathology Lab Med. 2013;137:1191-1198. Le Chevalier T, et al. Adjuvant Chemotherapy for Resectable Non-Small-Cell Lung Cancer: Where is it Going? Ann Oncol. 2010;21:vii196-vii198. Goldstraw P, et al. The IASLC Lung Cancer Staging Project: Proposals for Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11(1):39-51. Sethi S, et al. Incidental Nodule Management – Should There Be a Formal Process? J Thorac Oncol. 2016:8;S494-S497. LUNGevity Foundation. Screening and Early Detection. Available at https://lungevity.org/for-patients-caregivers/lung-cancer-101/screening-early-detection . Accessed March 2023. Pignon et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26:3552-3559.

Phase 3Clinical ResultASCOPhase 2

17 May 2023

·www.biospace.com

TAGRISSO® (osimertinib) plus chemotherapy demonstrated strong improvement in progression-free survival for patients with EGFR-mutated advanced lung cancer in FLAURA2 Phase III trial

Results support potential for a new treatment option that builds on the benefit of first-line standard of care TAGRISSO monotherapy WILMINGTON, Del.--(BUSINESS WIRE)-- Positive high-level results from the FLAURA2 Phase III trial showed AstraZeneca’s TAGRISSO® (osimertinib) in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to TAGRISSO alone for patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC). Safety results and discontinuation rates due to adverse events were consistent with the established profiles of each medicine. At the time of this analysis, the overall survival (OS) data were immature and will be formally assessed at a subsequent analysis. Each year, there are an estimated 2.2 million people diagnosed with lung cancer globally with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.1-3 Approximately 70% of people are diagnosed with advanced NSCLC. Additionally, about 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.4-6 Pasi A. Jänne, MD, PhD, medical oncologist at Dana-Farber Cancer Institute and principal investigator for the FLAURA2 trial, said: “As the global standard of care for EGFR-mutated non-small cell lung cancer, osimertinib monotherapy has transformed the treatment landscape allowing many patients the opportunity to achieve improved survival. FLAURA2 provides compelling evidence that the addition of chemotherapy to osimertinib can provide a new option for patients and clinicians that further improves outcomes compared to osimertinib alone and as such, can further delay treatment resistance and disease progression.” Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “These significant FLAURA2 results show TAGRISSO has the potential to offer patients in the first-line setting a new treatment option that can extend the time they live without their disease progressing. This meaningfully builds on successive trials which have demonstrated improved clinical benefit with TAGRISSO in patients with EGFR-mutated lung cancer.” The data will be presented at a forthcoming medical meeting and shared with global health authorities. These results add to the extensive body of evidence for TAGRISSO in EGFRm NSCLC, which has improved patient outcomes in both early-stage disease in the ADAURA Phase III trial and late-stage disease in the FLAURA Phase III trial, TAGRISSO has also shown proven clinical activity in treating central nervous system (CNS) metastases across settings. As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, TAGRISSO is also being investigated in unresectable NSCLC in the pivotal LAURA Phase III trial, with results expected later this year. IMPORTANT SAFETY INFORMATION There are no contraindications for TAGRISSO Interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of the 1479 TAGRISSO-treated patients; 0.3% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed Heart rate-corrected QT (QTc) interval prolongation occurs in TAGRISSO-treated patients. Of the 1479 TAGRISSO-treated patients in clinical trials, 0.8% were found to have a QTc >500 msec, and 3.1% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia Cardiomyopathy occurred in 3% of the 1479 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 3.2% of 1233 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of TAGRISSO-treated patients experienced LVEF decreases ≥10% from baseline and a drop to <50%. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO Keratitis was reported in 0.7% of 1479 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist Postmarketing cases consistent with Stevens-Johnson syndrome (SJS) and erythema multiforme major (EMM) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if SJS or EMM is suspected and permanently discontinue if confirmed Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.07% of 1479) and post marketing. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO. Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose Most common (≥20%) adverse reactions, including laboratory abnormalities, were leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough INDICATIONS TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test TAGRISSO is indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy Please see complete Prescription Information, including Patient Information for TAGRISSO. You may report side effects related to AstraZeneca products by clicking here. Notes Lung cancer Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer.2 The majority of all NSCLC patients are diagnosed with advanced disease.7 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signaling pathways that drive the growth of tumor cells.8 FLAURA2 FLAURA2 is a randomized, open-label, multi-center, global Phase III trial in the 1st-line treatment of 586 patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with TAGRISSO 80mg once daily oral tablets in combination with chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)) every three weeks for four cycles, followed by TAGRISSO with pemetrexed maintenance every three weeks. The trial was enrolled in more than 150 centers across more than 20 countries, including in the US, Europe, South America and Asia. This is the final analysis of the primary endpoint of PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS. TAGRISSO® TAGRISSO®(osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against CNS metastases. AstraZeneca continues to explore TAGRISSO as a treatment for patients across multiple stages of EGFRm NSCLC. TAGRISSO is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. These include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage (IB, II and IIIA) EGFRm NSCLC, where TAGRISSO recently demonstrated a statistically significant and clinically meaningful OS benefit. In addition to investigating TAGRISSO and chemotherapy in late-stage disease (FLAURA2), AstraZeneca has several ongoing Phase III trials focused on earlier stages of lung cancer. TAGRISSO is being tested in the neoadjuvant resectable setting (NeoADAURA), in the Stage IA2-IA3 adjuvant resectable setting (ADAURA2), and in the Stage III locally advanced unresectable setting (LAURA). The Company is also researching ways to address tumor mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test TAGRISSO given concomitantly with savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines. AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in the resistant and advanced settings. By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most. The Company's comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations, including tremelimumab and gefitinib; durvalumab and tremelimumab; fam-trastuzumab deruxtecan-nxki and datopotamab deruxtecan in collaboration with Daiichi Sankyo; savolitinib in collaboration with HUTCHMED; as well as a pipeline of potential new medicines and combinations across diverse mechanisms of action. AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer, including and beyond treatment. AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients. The Company’s focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyze changes in the practice of medicine and transform the patient experience. AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialization of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit and follow us on Twitter @AstraZenecaUS. References World Health Organization. International Agency for Research on Cancer. Lung Fact Sheet. Available at: . Accessed May 2023. LUNGevity Foundation. Types of Lung Cancer. Available at: . Accessed May 2023. Cheema PK, et al. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol. 2019;26(1):37-42. Szumera-Ciećkiewicz A, et al. EGFR Mutation Testing on Cytological and Histological Samples in Non-Small Cell Lung Cancer: a Polish, Single Institution Study and Systematic Review of European Incidence. Int J Clin Exp Pathol. 2013:6;2800-12. Keedy VL, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Epidermal Growth Factor Receptor (EGFR) Mutation Testing for Patients with Advanced Non-Small-Cell Lung Cancer Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. J Clin Oncol. 2011:29;2121-27. Ellison G, et al. EGFR Mutation Testing in Lung Cancer: a Review of Available Methods and Their Use for Analysis of Tumor Tissue and Cytology Samples. J Clin Pathol. 2013:66;79-89. Cagle P, et al. Lung Cancer Biomarkers: Present Status and Future Developments. Archives Pathology Lab Med. 2013;137:1191-1198. Cross DA, et al. AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer. Cancer Discov. 2014;4(9):1046-1061

Phase 3Clinical ResultASCODrug Approval

100 Deals associated with Methionine

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KEGG	Wiki	ATC	Drug Bank
D00019	Methionine	V03AB26	DB00134

R&D Status

10 top approved records.

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Indication	Country/Location	Organization	Date
Poisoning	-	-	-

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2023	Not Applicable	Diabetes Mellitus, Type 2 \| Colorectal Cancer	1,858	Met intake group	lracpldnsg(wlzgaejtzb) = zgkadkqwvn frksmmvpvx (nbqpjbpkuw ) View more	-	04 Apr 2023
				Non-intake group	lracpldnsg(wlzgaejtzb) = soqhegpyut frksmmvpvx (nbqpjbpkuw ) View more
ASTRO	Not Applicable	Brain Cancer	-	Methionine (CTV-Gd (20 mm))	(ixxudltvgj) = oklnzxwqfd daekalavae (wnzmtjffrw )	-	01 Sep 2019
				Methionine (CTV-T2 (20 mm))	(ixxudltvgj) = qyqiwxftqb daekalavae (wnzmtjffrw ) View more
ADA2019	Not Applicable	Polycystic Ovary Syndrome	88	Benaglutide 0.2 mg ih tid + MET 1000 mg bid	(dpbexpxpxc) = ytfdpxmlue iszpxvkjqz (yqaefhawlw ) View more	-	01 Jun 2019
				Exenatide 10ug ih bid + MET 1000 mg bid	(dpbexpxpxc) = qcisaoouor iszpxvkjqz (yqaefhawlw ) View more
NCT02526524 (CTgov)	Phase 2	Diabetes Mellitus, Type 2	571	Met DR (600 mg Met DR qAM)	fdbfzcwopt(cswoctpcjf) = xuiraswjcp cpbcxxzjlx (rknvgcpinp, fzlwqbcrfc - bvqxxkuopm) View more	-	27 Apr 2018
				Met DR (900 mg Met DR qAM)	fdbfzcwopt(cswoctpcjf) = qedqgboxdy cpbcxxzjlx (rknvgcpinp, zvnqrjgnei - qgclelmpdk) View more
NCT01804842 (CTgov)	Phase 1/2	Diabetes Mellitus, Type 2	26	Met DR (500 mg Met DR BID)	ngsrqzkyja(tmavvgtwzm) = nrusctykhv lziwujkdgh (lmsnqjmaic, zgyyvtmszb - nqpkoqviwc) View more	-	07 Apr 2016
				Met DR (1000 mg Met DR qAM)	ngsrqzkyja(tmavvgtwzm) = khybasfeky lziwujkdgh (lmsnqjmaic, xysntnztxh - rwgcejbmiw) View more
NCT02291510 (CTgov)	Phase 1	-	20	Met DR (500 mg Met DR BID)	wvbtemkldy(fmnfgflcha) = cevgwnaydk utegyhitzj (kgqzbybjtf, cwfsnivxkf - mnfuxdxgmk) View more	-	21 Sep 2015
				Met DR (1000 mg Met DR BID)	wvbtemkldy(fmnfgflcha) = equtookatp utegyhitzj (kgqzbybjtf, wnphisvfuz - tkiqdwgqii) View more
ASCO2012	Not Applicable	Adjuvant	-	Adjuvant Se-Met + IM + Levothyroxine	(pzczycjwmt) = rmviwsmktl dbaygskndg (zdmluqqkew )	-	20 May 2012
ASCO2005	Not Applicable	-	-	MGBG (Methionine poor medium)	xqlpoudxnb(pnudiauzkw) = hwhebkadkj uvehszpnis (tmaupksntr ) View more	-	01 Jun 2005
				Methionine restriction + MGBG	xqlpoudxnb(pnudiauzkw) = vuzebozejk uvehszpnis (tmaupksntr ) View more

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