Ursolic Acid

更进一步的探索显示，S1P通过提高肠道中asah-1基因的转录来发挥代际遗传中的调控作用。 近期，《自然·细胞生物学》杂志上，莫纳什大学Roger Pocock教授带领的研究团队发表了一项研究成果，揭示了母亲的饮食对后代，甚至后代的后代的轴突保护作用，研究的第一作者为王文悦博士。 他们基于秀丽隐杆线虫模型发现，母亲补充熊果酸可以改善两代后代的轴突运输，减少轴突断裂，并且揭示了其中机制和关键的介导因子——一种名为鞘氨醇-1-磷酸的鞘脂[1]。 轴突对于维持健康的神经元非常重要，蛋白质和脂质等物质都需要轴突运输，而其中的微管是实现轴突运输、运输物质移动的重要机制之一，随着年龄增长，轴突会逐渐变得脆弱，这也是大脑功能障碍和神经变性的原因之一。 研究团队希望能找到保护轴突，避免轴突随年龄增长而断裂的天然物质，在筛选过程中，他们锁定了熊果酸，这种在苹果，以及罗勒、迷迭香和百里香等草本植物中存在的物质能够抑制轴突脆弱性，线虫母亲补充后，后代的后外侧机械感觉（PLM）神经元轴突断裂显著减少，发挥功能的时期在卵母细胞产生和成熟期间，对后代轴突的保护可以跨越两代。 线虫母亲补充熊果酸（UA）后，两代后代（F1和F2）的神经元轴突断裂显著减少 确定了熊果酸的保护作用后，接下来就是要搞清楚其中的机制。 由于功能时期为卵母细胞产生和成熟期间，研究人员猜测，熊果酸可能影响了卵黄对卵母细胞的供给。线虫肠道中合成的卵黄含有脂质和脂蛋白，可以为卵母细胞和胚胎发育提供营养，卵母细胞通过内吞作用吸收卵黄，需要RME-2受体介导，研究人员也确实发现，RME-2是熊果酸降低神经元脆弱性所必需的，为肠道-卵母细胞的运输提供了必要的支持。 补充熊果酸增加了鞘脂生物合成酶——酸性神经酰胺酶-1（asah-1）基因的表达，由两个转录因子PQM-1和CEH-60调控。 包括神经酰胺在内的鞘脂具有多种细胞功能，实验显示，神经酰胺或其衍生物对轴突健康很重要。鞘脂稳态通过从头合成或补救途径维持，在补救途径中，神经酰胺被ASAH水解产生鞘氨醇，再由鞘氨醇激酶（SphK）磷酸化产生鞘氨醇-1-磷酸（S1P），SphK-1的表达减少了轴突断裂，反之，则抑制了ASAH-1对轴突的保护作用。这表明，熊果酸对轴突的保护作用要依赖于S1P。 S1P的直接补充显著降低了轴突脆弱性，功能时期和代际效应与熊果酸相同，并且依赖于RME-2介导的肠道-卵母细胞运输。 线虫母亲直接补充S1P后对后代的轴突保护作用与补充熊果酸类似 从具体的功能表现上来说，在遗传因素导致的轴突微管不稳定情况下，熊果酸和S1P促进了蛋白质沿轴突的运输，即使在遗传因素基础上继续施加化学物质影响，熊果酸和S1P也可以减少轴突断裂，也就是说，即使存在两种脆弱因素，熊果酸和S1P仍然可以稳健地降低轴突脆弱性。 不但如此，这种对轴突的保护效果还具有普遍性，在不同的遗传模型，以及D型GABA能运动神经元和PVQ中间神经元中，熊果酸和S1P均减少了轴突断裂。 更进一步的探索显示，S1P通过提高肠道中asah-1基因的转录来发挥代际遗传中的调控作用。 也就是说，线虫母亲补充天然物质熊果酸后产生的保护性分子可以由肠道转运至卵母细胞，在两代后代中改善轴突脆弱性，并且这种保护作用具有普遍性，可以跨遗传因素和神经元类型发挥作用。 Pocock教授表示，这是首次证实脂质/脂肪是可遗传的，此外，这一研究结果意味着，母亲的饮食不仅会影响自身后代的大脑，还可能产生潜在的连续代际影响，支持了孕期健康饮食以赋予后代最佳大脑发育和健康的重要性[2]。 参考文献： [1] Wang W, Sherry T, Cheng X, et al. An intestinal sphingolipid confers intergenerational neuroprotection[J]. Nature Cell Biology, 2023: 1-12. [2] https://www.monash.edu/news/articles/a-mothers-diet-can-protect-her-grandchildrens-brains-study

Top-line data from RESPONSE Phase 3 study in PBC expected by end of September 2023 IDEAL clinical trial actively recruiting Conference call and webcast today at 4:30 p.m. ET NEWARK, Calif., Aug. 10, 2023 (GLOBE NEWSWIRE) -- CymaBay Therapeutics, Inc. (NASDAQ: CBAY), a clinical-stage biopharmaceutical company focused on developing therapies for liver and other chronic diseases with high unmet need, announced today corporate updates and financial results for the second quarter ended June 30, 2023. Sujal Shah, President and CEO of CymaBay, stated, “I’m incredibly proud of the progress our teams have made thus far this year as we march towards our key and exciting milestone in the third quarter when we expect to report top-line results from RESPONSE, our global phase 3 registration study of seladelpar in patients with primary biliary cholangitis (PBC). With RESPONSE nearing completion and ASSURE having enrolled over 300 patients to date, we believe the seladelpar development program in PBC is one of the most robust development programs in PBC ever conducted. We continue to believe seladelpar has the potential to be a differentiated second-line treatment option offering patients benefits on markers of disease associated with risk of progression and on symptoms. As announced earlier today, we are now also actively recruiting patients in IDEAL, a study to evaluate seladelpar’s effects on biochemical normalization in PBC patients who only achieve a partial response to first-line treatment. We believe data from IDEAL has the potential to reset expectations for second-line treatment in PBC. In anticipation of a successful data readout in RESPONSE and regulatory acceptance, our organizational build efforts are also underway as we start to put together key components of our commercial and medical affairs infrastructure.” Corporate Updates: Announced the initiation of a 52-week, placebo-controlled, randomized, Phase 3 study Intended to Determine the Effects of seladelpar on normalization of Alkaline phosphatase Levels in subjects with PBC (IDEAL). This study will target enrolling 75 patients, who have an incomplete response or intolerance to ursodeoxychoic acid (UDCA) as well as ALP greater than upper limit of normal (ULN) but less than 1.67xULN, in a 2:1 randomization to oral, once daily seladelpar 10 mg or placebo. Featured results of our studies at The International Liver Congress™ 2023 of the European Association for the Study of Liver (EASL). The presentation reported: Treatment with seladelpar was found to be correlated with decreases in pruritus and Interleukin-31 (IL-31) levels in patients with PBC. We believe this to be the first intervention in PBC to show this correlation. IL-31 is a cytokine known to play a significant role in pruritus in a variety of other diseases. Transcriptomics data produced from two distinct fibrosis models, coupled with a platform capable of searching publicly available databases, revealed new aspects of the action of seladelpar to reduce established fibrosis. An analysis revealing that patients previously treated with UDCA, and having elevated levels of alkaline phosphatase (ALP) that do not currently qualify for second-line treatment, very often had additional factors for risk of disease progression. This highlights the potential for a broader population of patients that may benefit from second-line therapy. Enrollment completed in a Phase 2a proof-of-pharmacology study to evaluate the potential for MBX-2982, a GPR119 agonist, to prevent hypoglycemia in patients with type 1 diabetes. The study is being fully funded by The Leona M. and Harry B. Helmsley Charitable Trust with CymaBay retaining full rights to MBX-2982. Top-line results expected by year-end 2023. Financial Updates: Recognized $31.0 million of collaboration revenue in the second quarter of 2023 related to the $34.2 million upfront fee received from the collaboration and license agreement with Kaken Pharmaceutical Co., Ltd. in January 2023 for the development and commercialization of seladelpar in Japan. Held $213.8 million in cash, cash equivalents and investments as of June 30, 2023. We believe that cash and investments on hand are sufficient to fund CymaBay’s operating plan through the third quarter of 2024. Second Quarter and Six Months Ended June 30, 2023 Financial Results Collaboration revenue recognized for the three and six months ended June 30, 2023 was $31.0 million, on completion of the initial technology transfer associated with the license to develop and commercialize seladelpar in Japan. Of the $34.2M upfront payment received from Kaken, $2.7 million remains deferred and will be recognized upon completion of the Company’s ongoing clinical data delivery and CMC development performance obligations. Research and development expenses for the three months ended June 30, 2023, and 2022 were $19.5 million and $17.9 million, respectively. Research and development expenses for the six months ended June 30, 2023 were $38.1 million and $36.3 million, respectively. Research and development expenses for the three- and six-month periods ended June 30, 2023 increased compared to the corresponding periods in 2022 as we continue to hire additional research and development personnel and engage external contractors to support our clinical studies and potential regulatory submissions. General and administrative expenses for the three months ended June 30, 2023 and 2022 were $11.6 million and $5.9 million, respectively. General and administrative expenses for the six months ended June 30, 2023 and 2022 were $19.9 million and $12.0 million, respectively. General and administrative expenses for the three and six months ended June 30, 2023 were higher than the corresponding period in 2022 due to an increase in headcount as we continued to add administrative personnel and expand our infrastructure to support our drug development activities and prepare for potential commercialization of seladelpar in PBC. Net loss for the three months ended June 30, 2023 and 2022 was $0.8 million and $27.1 million, or ($0.01) and ($0.31) per share, respectively. Net loss for the six months ended June 30, 2023 was $29.6 million and $54.9 million, or ($0.30) and ($0.62), respectively. Net loss for the three- and six-month periods ended June 30, 2023 was lower than the corresponding periods in 2022 due primarily to the recognition of $31.0 million of collaboration revenue during the three months ended June 30, 2023 and higher interest income earned on our investments and other income due to refundable tax credits, offset in part by an increase in operating expenses. Overall, we expect operating expenses to increase in the future as we continue to support our ongoing drug development activities and expand on initiatives to plan and prepare for potential commercialization of seladelpar in PBC. Conference Call Details CymaBay will host a conference call today at 4:30 p.m. ET to discuss first quarter financial results and provide a business update. To access the live conference call, please dial 1-877-308-2053 from the U.S. and Canada, or 1-212-231-2921 internationally, Conference ID # 22027740. To access the live and subsequently archived webcast of the conference call, go to the Investors section of the company's website at . About CymaBay CymaBay Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on improving the lives of people with liver and other chronic diseases that have high unmet medical need through a pipeline of innovative therapies. Our deep understanding of the underlying mechanisms of liver inflammation and fibrosis, and the unique targets that play a role in their progression, have helped us receive breakthrough therapy designation (U.S. Food and Drug Administration), Priority Medicines status (European Medicines Agency) and orphan drug status (U.S. and Europe) for seladelpar, a first-in-class investigational treatment for people with primary biliary cholangitis (PBC). Our evidence-based decision-making and commitment to the highest quality standards reflect our relentless dedication to the people, families and communities we serve. To learn more, visit and follow us on Twitter and Linkedin. Cautionary Statements Any statements made in this press release regarding the potential approval, launch and commercialization of seladelpar or timing or plans in regard thereto, including the timing of the release of top-line data from RESPONSE, as well as statements regarding the Company’s expected cash runway, potential benefits of seladelpar, potential of IDEAL to reset expectations for second-line treatment in PBC, completion of ongoing clinical trials and subsequent regulatory submissions are forward-looking statements that are subject to risks and uncertainties. Actual results and the timing of events regarding the further development of seladelpar could differ materially from those anticipated in such forward-looking statements as a result of risks and uncertainties, which include, without limitation, risks related to: the success, cost and timing of any of CymaBay's product development activities, including clinical trials; effects observed in trials to date that may not be repeated in the future; any delays or inability to obtain or maintain regulatory approval of CymaBay's product candidates in the United States or worldwide; and the ability of CymaBay to obtain sufficient financing to complete development, regulatory approval and commercialization of its product candidates in the United States and worldwide. Additional risks relating to CymaBay are contained in CymaBay's filings with the Securities and Exchange Commission, including without limitation its most recent Annual Report on Form 10-K and other documents subsequently filed with or furnished to the Securities and Exchange Commission. CymaBay disclaims any obligation to update these forward-looking statements except as required by law. For additional information about CymaBay, visit . Public Relations Contact: Theresa Dolge Evoke Kyne (609) 915-2156 Theresa.Dolge@evokegroup.com Investor Relations Contact: Hans Vitzthum LifeSci Advisors, LLC (617) 430-7578 Hans@LifeSciAdvisors.com CymaBay Therapeutics, Inc. Financial Results (In thousands, except share and per share information) Quarter Ended Six Months Ended June 30, June 30, 2023 2022 2023 2022 (unaudited) (unaudited) (unaudited) (unaudited) Collaboration revenue 31,016 - 31,016 $ - Operating expenses: Research and development 19,537 17,891 38,088 36,306 General and administrative 11,578 5,878 19,902 11,965 Total operating expenses 31,115 23,769 57,990 48,271 Loss from operations (99 ) (23,769 ) (26,974 ) (48,271 ) Other income (expense), net: Interest income 2,627 321 4,640 419 Interest expense (4,618 ) (3,648 ) (9,021 ) (7,013 ) Other income 1,282 2 1,769 2 Total other income (expense), net (709 ) (3,325 ) (2,612 ) (6,592 ) Net loss $ (808 ) $ (27,094 ) $ (29,586 ) $ (54,863 ) Basic and diluted net loss per common share $ (0.01 ) $ (0.31 ) $ (0.30 ) $ (0.62 ) Weighted average common shares outstanding used to calculate basic and diluted net loss per common share 102,150,390 87,802,939 100,072,281 87,802,939 CymaBay Therapeutics, Inc. Balance Sheet Data (in thousands) June 30, December 31, 2023 2022 (unaudited) Cash, cash equivalents and marketable securities $ 213,844 $ 135,485 Working capital 206,177 122,632 Total assets 226,650 141,852 Total liabilities 118,242 105,698 Common stock and additional paid-in capital 1,010,975 909,337 Total stockholders’ equity 108,408 36,154