Oxysterols(Centre National de la Recherche Scientifique)

-- Observed reductions of 11% and 12% in 24- and 27-hydroxycholesterol in cerebrospinal fluid (“CSF”), respectively, indicating potential improvement of cholesterol metabolism in the brain -- -- Observed 8% increase in Aβ42/40 ratio, a key biomarker of AD risk, suggesting improvement in disease pathology -- NAARDEN, The Netherlands and MIAMI, Sept. 21, 2023 (GLOBE NEWSWIRE) -- NewAmsterdam Pharma Company N.V. (Nasdaq: NAMS or “NewAmsterdam” or the “Company”), a clinical-stage biopharmaceutical company developing oral, non-statin medicines for patients at high risk of cardiovascular disease with residual elevation of low-density lipoprotein cholesterol (“LDL-C”), for whom existing therapies are not sufficiently effective or well-tolerated, today announced initial data from its Phase 2a clinical trial evaluating obicetrapib in patients with early Alzheimer’s disease (“AD”) and at least one copy of the apolipoprotein E4 mutation (“ApoE4”). This Phase 2a trial was designed to explore the effects of obicetrapib on lipid metabolism in the brains of early AD patients who are ApoE4 carriers. Two key biomarkers measured in the trial include 24- and 27-hydroxycholesterol; increases in these oxysterols over time have been observed to lead to a rise in cognitive and related functional impairment. As such, NewAmsterdam believes reductions of 24- and 27-hydroxycholesterol in the CSF may indicate improved cholesterol metabolism in the brain and may lead to improved cognitive function. In addition, the Phase 2a trial assessed the Aβ42/40 ratio and plasma pTau181, also believed to be biomarkers of AD, with lower levels of Aβ42/40 and increased levels of pTau181 having been associated with a greater risk of AD. This trial builds on observations from NewAmsterdam’s preclinical studies and third-party genetic studies that inhibiting cholesteryl ester transfer protein (“CETP”) may protect against ApoE4-associated AD risk by preventing the accumulation of amyloid plaque in the brain through improved cholesterol metabolism and, as a result, potentially slow disease progression. “These data represent an important first step in determining the role of lipid metabolism in the brain,” said Jeffrey Cummings, M.D., Director of the Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada, Las Vegas. “Approximately two thirds of patients with Alzheimer’s dementia carry at least one copy of the ApoE4 gene and CETP loss-of-function mutations have been shown to protect against ApoE4-associated AD risk. These data warrant further study of CETP inhibition as a potential mechanism to ameliorate ApoE4-associated AD risk.” Initial Data from the Phase 2a Alzheimer’s Trial “We are encouraged by our initial data, in which we observed reductions in CSF levels of 24- and 27-hydroxycholesterol in the 13 patients treated in the trial. We believe increased CSF levels of these oxysterols may be linked to neuroinflammation and Alzheimer’s pathology,” said Michael Davidson, M.D., Chief Executive Officer of NewAmsterdam. “We are particularly pleased that this observed reduction in 24- and 27-hydroxycholesterol was paired with an eight percent improvement in the Aβ42/40 ratio. Based on these initial results, we believe obicetrapib could offer a meaningful advancement for a high-risk patient population with limited available treatment options and look forward to working to further characterize its potential for AD in an efficient, cost-effective manner through our ongoing clinical trials.” The open-label and single-arm trial was designed to assess the pharmacodynamics, pharmacokinetics, safety and tolerability of obicetrapib 10 mg in early AD patients carrying at least one copy of ApoE4. A total of 13 patients were given 10 mg obicetrapib and followed for 24 weeks. NewAmsterdam observed reductions in the levels of 24- and 27-hydroxycholestrol of 11% and 12%, respectively, in the CSF. In addition, an increase of 8% in the Aβ42/40 ratio in patient’s plasma was observed and pTau181 levels were observed to be stable. Overall, obicetrapib was observed to be well-tolerated. No serious adverse events (“AEs”) were reported, nor were any AEs considered to be related to the study drug. “Together, we believe these observations suggest that potent CETP inhibition may offer a novel approach to reducing the risk of AD in ApoE4 carriers. In this small trial, treatment with obicetrapib was observed to reduce levels of 24- and 27-hydrocholestrol and increase the ratio of Aβ42/40 in plasma, supporting our belief that improved brain cholesterol metabolism correlates with removal of amyloid beta peptides which ultimately might lead to improved cognition,” said John Kastelein, M.D., Ph.D., FESC, Chief Scientific Officer of NewAmsterdam. NewAmsterdam anticipates sharing the full results of this Phase 2a clinical trial in a forthcoming publication or in a presentation at an upcoming medical meeting and plans to seek feedback from the U.S. Food and Drug Administration to inform the potential further development of obicetrapib for the treatment of AD. About ObicetrapibObicetrapib is a novel, oral, low-dose CETP inhibitor that NewAmsterdam is developing to overcome the limitations of current LDL-lowering treatments. The Company believes that obicetrapib has the potential to be a once-daily oral CETP inhibitor for lowering LDL-C, if approved. In the Company’s Phase 2b ROSE trial, obicetrapib demonstrated a 51% lowering of LDL-C from baseline at a 10 mg dose level on top of high-intensity statins and, in the Company’s Phase 2 ROSE2 trial, the combination of a 10 mg dose of obicetrapib and a 10 mg dose of ezetimibe demonstrated a 63% lowering of LDL-C from baseline. In all five of the Company’s Phase 2 trials, ROSE2, TULIP, ROSE, OCEAN, and TA-8995-203, evaluating obicetrapib as monotherapy or combination therapy, the Company observed statistically significant LDL-lowering combined with a side effect profile similar to that of placebo, including no increase in blood pressure or muscle related side effects. Obicetrapib has demonstrated strong tolerability in more than 800 patients with elevated lipid levels (“dyslipidemia”) in NewAmsterdam’s clinical trials to date. The Company is conducting two Phase 3 pivotal trials, BROADWAY and BROOKLYN, to evaluate obicetrapib as a monotherapy used as an adjunct to maximally tolerated lipid-lowering therapies to provide additional LDL-lowering for high-risk cardiovascular disease (“CVD”) patients. The Company began enrolling patients in BROADWAY in January 2022 and in BROOKLYN in July 2022 and completed enrollment of BROOKLYN in April 2023 and BROADWAY in July 2023. The Company also commenced the Phase 3 PREVAIL cardiovascular outcomes trial in March 2022, which is designed to assess the potential of obicetrapib to reduce occurrences of major adverse cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and non-elective coronary revascularization. About NewAmsterdam Based in the Netherlands, NewAmsterdam (Nasdaq: NAMS) is a clinical-stage biopharmaceutical company whose mission is to improve patient care in populations with metabolic diseases where currently approved therapies have not been sufficiently adequate or well tolerated. NewAmsterdam seeks to fill a significant unmet need for a safe, cost-effective and convenient LDL-lowering therapy as an adjunct to statins, a class of lipid-lowering medications that are the current standard of care for high-risk CVD patients with high cholesterol. NewAmsterdam is investigating obicetrapib, an oral, low-dose and once-daily CETP inhibitor, as the preferred LDL-C lowering therapy to be used as an adjunct to maximally tolerated statin therapy for high-risk cardiovascular disease patients. Forward-Looking Statements Certain statements included in this document that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements generally are accompanied by words such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “intend,” “expect,” “should,” “would,” “plan,” “predict,” “potential,” “seem,” “seek,” “future,” “outlook” and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding the Company’s business and strategic plans, the Company’s commercial opportunity, the therapeutic and curative potential of the Company’s product candidate, the Company’s clinical trials and the timing for enrolling patients, the timing and forums for announcing data, the achievement and timing of regulatory approvals, and plans for commercialization. These statements are based on various assumptions, whether or not identified in this document, and on the current expectations of the Company’s management and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as and must not be relied on as a guarantee, an assurance, a prediction, or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and may differ from assumptions. Many actual events and circumstances are beyond the control of the Company. These forward-looking statements are subject to a number of risks and uncertainties, including changes in domestic and foreign business, market, financial, political, and legal conditions; risks related to the approval of the Company’s product candidate and the timing of expected regulatory and business milestones, including potential commercialization; whether topline, initial or preliminary results from a particular clinical trial will be predictive of the final results of that trial and whether results of early clinical trials will be indicative of the results of later clinical trials; ability to negotiate definitive contractual arrangements with potential customers; the impact of competitive product candidates; ability to obtain sufficient supply of materials; global economic and political conditions, including the Russia-Ukraine conflict; the effects of competition on the Company’s future business; and those factors described in the Company’s public filings with the Securities Exchange Commission. Additional risks related to the Company’s business include, but are not limited to: uncertainty regarding outcomes of the Company’s ongoing clinical trials, particularly as they relate to regulatory review and potential approval for its product candidate; risks associated with the Company’s efforts to commercialize a product candidate; the Company’s ability to negotiate and enter into definitive agreements on favorable terms, if at all; the impact of competing product candidates on the Company’s business; intellectual property related claims; the Company’s ability to attract and retain qualified personnel; ability to continue to source the raw materials for its product candidate. If any of these risks materialize or the Company’s assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. There may be additional risks that the Company does not presently know or that the Company currently believes are immaterial that could also cause actual results to differ from those contained in the forward-looking statements. In addition, forward-looking statements reflect the Company’s expectations, plans, or forecasts of future events and views as of the date of this document and are qualified in their entirety by reference to the cautionary statements herein. The Company anticipates that subsequent events and developments may cause the Company’s assessments to change. These forward-looking statements should not be relied upon as representing the Company’s assessment as of any date subsequent to the date of this communication. Accordingly, undue reliance should not be placed upon the forward-looking statements. Neither the Company nor any of its affiliates undertakes any obligation to update these forward-looking statements, except as may be required by law. Company Contact Matthew Philippe matthew.philippe@newamsterdampharma.com Media Contact Spectrum Science on behalf of NewAmsterdam Jenn Gordon P: 1-202-957-7795 jgordon@spectrumscience.com Investor Contact Stern Investor Relations on behalf of NewAmsterdam Hannah Deresiewicz P: 1 212-362-1200 hannah.deresiewicz@sternir.com

免疫抑制性TME对DC功能的影响方向包括：清除功能性DC、抑制DC关键功能、产生耐受性和免疫抑制细胞，以及通过下调作用于DC的趋化因子的产生，来预防DC与肿瘤细胞之间的直接接触。在TME内，几种肿瘤或间质来源的介质导致DC功能障碍，改变DC的分化、成熟、抗原提呈和寿命。肿瘤细胞产生的免疫抑制因子➤TME会诱导DC产生IL-10和IL-6，从而促进TME形成免疫抑制型。○ IL-10通过减少共刺激分子的表达将未成熟的DC转化为耐受性DC。比如在乳腺癌中，IL-10可以通过肿瘤浸润性CD103+ cDC1s抑制IL-12的产生，从而抑制T细胞反应。○ IL-6通过激活STAT3下调MHC II分子和CCR7的表达来抑制DC的成熟。➤肿瘤细胞产生的PGE2和TGF-β1都能够促进DC上调PD-L1，使其表现出免疫抑制作用。○ 其中，TGF-β是pDCs分化为免疫抑制表型的主要因素，能够抑制TLR9产生的IFN-α。阻断PD-L1/PD-1可缓解DC功能障碍，产生TNF-α、IL-12和IL-1β，并增强T细胞刺激能力。○ PGE2还被证明可以抑制DC的抗原提呈，并通过减少NK细胞的活性和趋化因子的产生来调节NK细胞介导cDC1s向TME的募集的趋势。➤VEGF影响DC与前体细胞的分化。VEGF水平升高会造成浸润和循环DC数量的减少。肿瘤来源的脂质：营造酸性微环境➤异常积累的肿瘤相关脂质能抑制DC迁移和抗原呈递功能。脂体(lipid body)是调节外源性抗原向CD8+淋巴细胞交叉递呈所必需的，但同时，DC中脂质的异常积累也是导致肿瘤中DC功能障碍的另一个机制。具体表现为，肿瘤相关DC会受到内质网应激反应因子XBP1的结构性激活，从而介导甘油三酯生物合成，导致脂质积累和抗肿瘤能力下降。○ 肿瘤细胞会产生高水平的乳酸，抑制IL-12的产生，并通过GPR81信号在体外和体内抑制DC依赖的抗原呈递。例如：乳腺癌模型中，乳酸抑制了Ⅰ型IFN的表达，并促进pDC通过IDO产生Treg细胞。例如：黑色素瘤来源的WNT5a配体被证明能以β−catenin依赖的方式上调局部DC的IDO的表达和活性，从而促进Tregs的分化。β-catenin+ 肿瘤细胞导致CCl4分泌减少，从而阻止CD103+cDc1募集到TME。○ 肿瘤来源的oxysterols可以下调CCR7的表达，从而抑制DC向次级淋巴组织的迁移，并抑制其产生抗肿瘤免疫反应。○ 氧化脂质还能通过隔离HSP70蛋白和减少MHC-I到质膜的移位来抑制交叉呈递。肿瘤进展中形成的缺氧/低氧型TME➤HIF-1α/CXCL12/CXCR4途径肿瘤生长过程中产生的缺氧诱导因子HIF-1α能促进pDC迁移，并诱导pDC分化为耐受表型，IFN-α产生能力降低，抗原提呈能力降低，Treg细胞扩增。➤HMGB1○ 宫颈癌的缺氧性TME还能上调HMGB1释放，导致TLR9介导的pDC分化，抑制细胞因子分泌，产生耐受性pDC。○ 垂死肿瘤细胞也表达HMGB1，此时HMGB1通过与DC上表达的受体TIM3的核酸竞争来抑制其抗肿瘤免疫反应。➤低氧/缺氧TME促进细胞外腺苷积累腺苷通过多种受体促进耐受性表型和未成熟pDC的募集并抑制细胞因子的分泌。在局部炎症微环境中，应激细胞增强的细胞内腺苷产生与活化或受损细胞释放腺嘌呤核苷酸的组合可导致组织腺苷浓度增加150倍。腺苷是通过激活白细胞表达的腺苷受体来调节炎症反应。○ 对于未成熟的pDC，腺苷激活A1受体并诱导其趋化性，这最初可能导致pDC募集到炎症部位。当病原体在这些位点遇到病原体时，PDC被激活并产生I型IFN和其他细胞因子，从而调节微环境并与先天性和抗原特异性效应细胞连接。○ 对于成熟的pDCs，其受体表达从A1转换到A2a的过程中，腺苷也通过cAMP提高A2a受体的表达，使pDCs对腺苷抗炎作用敏感，反而抑制成熟pDCs产生细胞因子的能力，并减弱导致组织损伤和疾病的慢性细胞激活的潜在有害影响。TME提高DC的促血管生长能力○ DC分泌的促血管生成因子主要为VEGF-A，还包括FGF2和ET-1。VEGF-A则需要CREB、HIF-1α和STAT3的激活才能产生。HIF-1α对DC的部分作用已经在上文中描述过，同时PGE2则能通过自分泌和旁分泌诱导CREB磷酸化。○ 一般来说，VEGF-A主要来源于cDC2和交叉型DC，pDCs产生较少。但肿瘤相关的pDC则能够通过产生TNF-α和CXCL8来促进体内的血管生成。○ β-defensin蛋白-CCR6轴则可以募集DC前体到肿瘤中，在VEGF暴露的环境下转化为具有促肿瘤功能的内皮样细胞。肿瘤来源的细胞外囊泡(TEV)TEV对DC有两面作用。Cell Mol Immunol (2023).➤首先，TEV能够转运肿瘤抗原，例如 Her2、Mart1、TRP、gp100、MHC-I 分子和DC激活的HSP等，从而刺激DC抗原提呈活性，引发抗原特异性CTL反应。肿瘤细胞可能将MHC/抗原复合物转移到DC上，这一过程被称为“cross-dressing”。从这个角度来看，TEV 似乎是在DC疫苗递送抗原的良好选择。➤但同时，TEV 也通过诱导MDSC的分化来抑制DC的抗肿瘤功能。○ 体外实验：来自黑色素瘤细胞系或晚期黑色素瘤患者血浆的TEV能抑制人 MoDCs分化，诱导其获得与MDSC相对应的表型。○ TEV也可能诱导MDSC，通过自分泌产生IL-6，以TLR2/MyD88依赖的方式触发STAT-3信号通路活性，对CD34+ 骨髓祖细胞向DC分化的过程产生抑制作用。➤CD105+ 肿瘤干细胞来源的TEV还能通过携带HLA-G抑制DC分化，与 T 细胞、NK细胞和DC上表达的抑制性受体结合。➤TEV还能诱导DC代谢重编程。TEV通过转移脂肪酸诱导DC免疫功能障碍，增加过氧化物酶体增殖物激活受体(PPAR)的表达。脂肪酸生物合成和氧化的增加会诱导线粒体氧化磷酸化，导致DC功能受损。小结DC本身是抗原呈递能力较强的APC，同时分泌的细胞因子相对温和，不会产生过于强大的促炎效果和过度激活，因此是整体考量比较有前景的细胞疗法。近期DC疫苗3期临床报道了突破性的好数据，国内也有一款mRNA和DC相结合的肿瘤疫苗产品申报临床。不过只要是肿瘤浸润免疫细胞，就难免受到TME的影响。效果如何改善还需从机制出发。相关文章：DC疫苗3期临床：60个月生存率提升一倍艰难的DC疫苗，喜迎突破...DC细胞分类、标志物、功能基础免疫实验-流式试剂参考文献：1.Del Prete, A., Salvi, V., Soriani, A. et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell Mol Immunol (2023). https://doi.org/10.1038/s41423-023-00990-62.Schnurr M,Toy T,etc. Role of adenosine receptors in regulating chemotaxis and cytokine production of plasmacytoid dendritic cells. Blood. 2004 Feb 15;103(4):1391-7. doi: 10.1182/blood-2003-06-1959. Epub 2003 Oct 9. PMID: 14551144.