Parunoflast

ENCINITAS, Calif., Sept. 19, 2022 (GLOBE NEWSWIRE) -- Ventyx Biosciences, Inc. (Nasdaq: VTYX) (“Ventyx”), a clinical-stage biopharmaceutical company focused on advancing novel oral therapies that address a range of inflammatory diseases with significant unmet medical need, announced today that it has entered into a stock purchase agreement for the sale of 5,350,000 shares of its common stock at an offering price of $33.00 per share in a private placement to certain qualified institutional buyers and institutional accredited investors. Gross proceeds of the private placement are expected to be approximately $176.6 million, before deducting placement agent fees and other expenses. The private placement is expected to close on September 20, 2022, subject to the satisfaction of customary closing conditions. The private placement was led by Redmile Group, with participation by Boxer Capital, Braidwell LP, EcoR1 Capital, Vivo Capital, Great Point Partners, LLC, Adage Capital Management, Logos Capital, Maven Investment Partners US, Driehaus Capital Management, Acuta Capital Partners, CaaS Capital Management, Woodline Partners LP, Walleye Capital and other investors, including two large mutual funds. Ventyx currently intends to use the net proceeds from the proposed private placement, together with existing cash and cash equivalents, to fund the clinical development of VTX958, VTX002, VTX2735 and VTX3232, the preclinical development of other programs, research activities and working capital and other general corporate purposes. With the proceeds from the private placement, Ventyx expects to extend its cash runway into 2025. This cash estimate is a preliminary estimate and is based on information available to management as of the date of this private placement, and these estimates could change. Morgan Stanley, Jefferies, Piper Sandler and LifeSci Capital are acting as the placement agents for the private placement. The securities being issued and sold in the private placement have not been registered under the Securities Act of 1933, as amended (the “Securities Act”), or any states' securities laws, and may not be offered or sold in the United States, except pursuant to an effective registration statement or an applicable exemption from the registration requirements of the Securities Act. Ventyx has agreed to file a registration statement with the Securities and Exchange Commission registering the resale of the shares of common stock issued in this private placement. This press release shall not constitute an offer to sell or the solicitation of an offer to buy any securities described herein, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or jurisdiction. About Ventyx Biosciences Ventyx is a clinical-stage biopharmaceutical company focused on developing innovative oral medicines for patients living with autoimmune and inflammatory disorders. We believe our ability to efficiently discover and develop differentiated drug candidates will allow us to address important unmet medical need with novel oral therapies that can shift immunology markets from injectable to oral drugs. Our current pipeline includes three clinical-stage internally discovered programs targeting TYK2, S1P1R and NLRP3, positioning us to become a leader in the development of oral immunology therapies. Ventyx is headquartered in Encinitas, California. Forward-Looking Statements Ventyx cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on Ventyx’s current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding management’s beliefs regarding the company’s cash runway following the closing of the private placement. The inclusion of forward-looking statements should not be regarded as a representation by Ventyx that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Ventyx’s business, including, without limitation, market risks and other market conditions; the risk that the conditions to the closing of the private placement are not satisfied; potential delays in the commencement, enrollment and completion of clinical trials; disruption to our operations from the ongoing global outbreak of the COVID-19 pandemic, or from the ongoing military conflict in Ukraine, including clinical trial delays; Ventyx’s dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing, which may be impacted by disruptions in the supply chain, including raw materials needed for manufacturing, animals used in research, delays in site activations and enrollment of clinical trials; the results of preclinical studies and early clinical trials are not necessarily predictive of future results; the success of Ventyx’s clinical trials and preclinical studies for its product candidates; interim results not necessarily being predictive of final results; the potential of one or more outcomes to materially change as the trial continues and more patient data become available and following more comprehensive audit and verification procedures; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; Ventyx’s ability to obtain and maintain intellectual property protection for its product candidates; the use of capital resources by Ventyx sooner than expected; and other risks described in Ventyx’s prior press releases and Ventyx’s filings with the Securities and Exchange Commission (SEC), including in Part II, Item 1A (Risk Factors) of Ventyx’s Quarterly Report on Form 10-Q filed on August 15, 2022, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Ventyx undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investor Relations Contact Patti BankManaging DirectorWestwicke Partners(415) 513-1284IR@ventyxbio.com

心血管领域的临床探索，正接连遭遇来自现实的重击。 7月底，IL-6抑制剂ziltivekimab首个心血管III期研究ZEUS折戟；9月7日，另外两项III期临床HERMES与ATHENA宣告提前终止，这款曾被寄予厚望的抗炎新星，遭遇了的“三连败”。 此前不久，备受关注的反义寡核苷酸疗法pelacarsen同样止步III期。两款分别站在抗炎、降脂前沿赛道的明星药物，陷入了高度相似的困境：替代终点指标均显著改善，却始终没能跨过心血管事件获益这道硬门槛。 这早已不被简单视为单款药物的研发失利。从Lp(a)到IL-6，替代终点与临床终点之间的转化鸿沟，正在对心血管领域两大疾病机制发起严苛检验。 尤其是IL-6，沿着炎症级联向上追溯，与之密切相关的、也是当前最热门的前沿抗炎靶点之一NLRP3，也被卷入这场关于“炎症假说”成色的重估。 01 Ziltivekimab三连败 Ziltivekimab的接连落败，既在意料之外，又在预期之内。 在机制层面，IL-6是学界公认的核心促炎因子，深度参与动脉粥样硬化的全程进展：它既能激活血管内皮细胞、促进炎症细胞募集浸润，也能干扰脂蛋白代谢、刺激肝脏生成CRP、纤维蛋白原等急性期反应物，最终推动斑块不稳定与血栓形成。 早在基因组学研究中，孟德尔随机化分析就曾给出过明确的因果提示：IL-6受体信号的异常增强，与冠心病发病风险显著正相关。这为靶点的遗传学合理性提供了关键支撑。 在II期RESCUE临床试验中，ziltivekimab更是展现出了极强的降炎效果：不同剂量组将患者的hs-CRP分别砍下了77%、88%和92%，而安慰剂组仅下降4%。 凭借如此强劲的抗炎表现，ziltivekimab被快速推进至大规模III期临床。而在首个III期结果读出后，诺和诺德便提示，该项目仍有较高风险。 风险首先在ZEUS研究中暴露。该研究纳入了6376名ASCVD、慢性肾病和炎症（hs-CRP≥2）患者。主要终点为3 point MACE（心血管死亡、非致死性心肌梗死、非致死性卒中）。7月31日，ZEUS主要结果公布，中位随访时间约3.7年，MACE风险比（HR）为0.99（95%CI:0.88-1.11），与安慰剂相比无统计学差异。 也就是说，药物精准抑制了IL-6通路，也大幅压低了hs-CRP这个经典炎症标志物，却没有给患者带来任何心血管事件层面的获益。 仅隔一个多月，ziltivekimab另外两项III期研究HERMES和ATHENA也被提前终止。 两项研究均是针对伴有炎症的射血分数保留或轻度降低型心衰患者。根据clinical数据，HERMES已完成了4899名患者入组，ATHENA则纳入约680名患者，原计划明年陆续完成。数据监测委员会评估后认为，两项研究的临床结局不大可能不同于ZEUS，继续推进已无临床意义。 不过，ziltivekimab的心血管开发并没有就此完全停止。另一项III期研究ARTEMIS仍在进行，针对的是急性心肌梗死患者，这也是ziltivekimab目前留在心血管领域的最后一个验证窗口。 02 IL-6为什么不行 Ziltivekimab的核心困境，不并非抗炎效果不足，而是生物学效应与临床获益的脱钩。也就是药物研发里的“替代终点陷阱”，与pelacarsen近期的遭遇并无二致。 从II期到III期，ziltivekimab降低hs-CRP的作用始终稳定且明确。作为心血管领域应用最广泛的炎症生物标志物，hs-CRP水平升高早已被证实与心血管事件风险增加、心力衰竭预后不良高度相关。但“能预测风险”和“降低它就能降低风险”，是两个完全不同的医学概念。 ZEUS的临床结果将这个关键问题暴露出来。理论上ziltivekimab能够有效抑制IL-6通路，并将hs-CRP水平显著压低，但从抗炎到降低心血管事件风险中间还隔着很多环节。 本质上，替代指标（hs-CRP）是“果”而非“因”。单纯压低这个标志物的数值，并不等于切断了疾病进展的核心动力。 除此之外，IL-6是炎症反应的下游效应因子，而非上游调控节点。动脉粥样硬化的发生发展，是IL-1β、TNF-α、IL-6等多条炎症通路共同作用的结果。单一阻断IL-6，只能抑制其中一条下游分支，不足以撼动整个疾病的炎症进程。 这一点在此前的研究中已有迹可循。秋水仙碱早期在接受PCI治疗的急性心肌梗死人群中，虽表现出明确的抗炎效应，却未能带来显著的心血管获益；而在针对稳定冠心病患者的LoDoCo2研究、针对心梗后患者的COLCOT研究中，秋水仙碱却显示出约30%的事件下降。这充分说明，抗炎治疗的疗效高度依赖疾病阶段与人群特征，不存在普适性的抗炎获益。 更上游的IL-1β靶点的成功，恰好形成了鲜明对照。CANTOS研究证实，IL-1β抑制剂卡纳单抗可降低15%的心血管事件风险，首次证明不依赖降脂的抗炎治疗也能减少心血管事件。与IL-6不同，IL-1β处于炎症级联的更上游位置，调控着下游多个炎症介质的释放，对疾病进程的影响力更强，这可能是其能够转化为临床硬终点获益的关键。 而广谱抗炎的失败，则从另一个维度划清了边界。CIRT研究显示，低剂量甲氨蝶呤虽能降低全身炎症指标，却未能减少心血管事件。这意味着，抗炎不是越强越好、越广越好，精准击中驱动疾病的关键节点，才是治疗有效的核心。 除了疗效的脱钩，安全性问题也进一步压缩了IL-6抑制剂的获益空间。ZEUS研究中，ziltivekimab组的严重感染发生率高于安慰剂组。IL-6是免疫系统的重要组成部分，对中性粒细胞的生成、活化以及获得性免疫反应的调控至关重要；过度抑制IL-6通路会导致外周血中性粒细胞减少，增加细菌、真菌感染及机会性感染的风险，使得药物的获益风险比进一步下降。 显然，炎症与动脉粥样硬化之间的关系，远比我们想象的复杂。 03 NLRP3被牵连？ 真正被卷入风波的，不止一个分子。 面对接连3项临床试验的失败，杰富瑞分析师表示：“研究失败使人们质疑降低IL-6/hsCRP是否是ASCVD的可行目标，并由此打击了位于IL-6上游的NLRP3理论。” NLRP3作为近年来药企争相布局的“明星靶点”，因其位于IL-1β和IL-6的上游，一度被视为心血管抗炎的终极解法。年初，礼来也给这个靶点再填了一把火，以12亿美元收购Ventyx Biosciences，将VTX3232、VTX2735收入囊中，在肥胖伴心血管风险人群的IIa期研究中，VTX3232能够显著降低hs-CRP和IL-6，而且这种变化并不依赖减重。 BioAge的BGE-102公布了降低炎症指标的早期信号，包括治疗14天后血清IL-6中位数下降44%。此外，还有罗氏、诺华等巨头也在布局NLRP3靶点。 如今，下游最核心的表达通路被证明无法换来MACE获益，整个“NLRP3→IL-1β/IL-6→hs-CRP”轴线的商业与临床价值，也被蒙上了一层阴影。 尽管种种质疑仍有待商榷，两者处于炎症通路的不同位置，作用机制也不相同。IL-6抑制剂主要针对单一的下游炎症因子，而NLRP3位于更上游，理论上能够影响IL-1β、IL-6等多个炎症介质。 并且，心血管炎症假说本身并未被证伪。早在诺华的CANTOS研究中，IL-1β单抗（卡纳单抗）就曾以确凿的数据证明，在不改变血脂水平的前提下，单纯靶向IL-1β通路可以使高危患者的心血管事件发生率显著下降15%。这证实了干预特定炎症通路确实具备改写心血管结局的可能。 短时间内ziltivekimab的失败或许会让NLRP3承受更大的压力，但还不足以否定这条路线。 然而，市场的恐慌却早已外溢。ZEUS数据读出当日，BioAge股价暴跌63%，Monte Rosa Therapeutics下跌27%。两家公司均拥有NLRP3抑制剂项目，其中BioAge的BGE102、Monte的NLRP3项目均在心血管领域有布局。 当市场过早将预期拉得太满，自然无法承受一丝一毫的打击。 04 向左？向右？ 复杂的炎症通路，让NLRP3这类更前沿的探索之路充满不确定性，但也赋予了它更多的可能性。 与此同时，ziltivekimab也给整个心血管抗炎赛道踩了一脚关键的刹车。真正值得反思的或许是，并不是所有与炎症相关的分子，都能成为有效的治疗靶点，哪怕机制理论“证据”十足。炎症通路中，有些是驱动疾病进展的核心引擎，有些只是疾病发生后的伴随标记；有些靶点在特定疾病阶段、特定人群中发挥关键作用，在另一些人群中却影响甚微。 而在此之前，市场或多或少对替代终点存在过度依赖。从血脂到炎症，替代终点凭借易测量、周期短的优势，成为研发早期的重要参考。但ziltivekimab的三连败、pelacarsen的折戟，都在反复提醒我们：替代终点终究只是替代，心血管事件硬终点的验证，才是衡量药物价值的唯一金标准。 从这个角度来说，科学探索的代价虽昂贵，但这场降温也并非全是坏事。它让药企们更审慎地思考靶点的成药性、适应症人群的选择、临床终点的设计，而不是盲目跟风投入资源。 从CANTOS首次证实抗炎治疗的心血管价值，到CIRT、秋水仙碱早期研究的反复，再到如今IL-6抑制剂的三连败，心血管抗炎假说正在一步步勾勒出自己的边界。 这条赛道的魅力在于，它为心血管疾病提供了降脂之外的全新治疗路径，但残酷也同样鲜明。 接下来，ARTEMIS研究能否为IL-6通路扳回一城，NLRP3靶点的临床数据能否验证上游抗炎的价值，将继续为心血管抗炎的谜团给出答案。