Sirolimus/Phenytoin/Methoxsalen

关注并星标CPHI制药在线胰腺癌是消化道常见恶性肿瘤之一，约90%是起源于腺管上皮的导管腺癌。由于症状隐匿、恶性程度高、致死率高，胰腺癌被称为“癌症之王”。据柳叶刀杂志记载，胰腺癌确诊后的五年生存率约10%，是预后最差的恶性肿瘤之一。据WHO国际癌症研究机构公布的数据，2020年全球胰腺癌新发病例数居所有癌症类型的第12位，死亡病例数居第7位，每年导致30多万患者的死亡。然而，胰腺癌早期诊断率不足5%，约60%的患者首诊时已转移，约30%的患者首诊时处于局部进展期。早期胰腺癌可以通过手术切除病灶，但大部分患者都在接受手术后一年复发。晚期胰腺癌以化疗为主，目前国际公认的一线化疗方案包括FOLFIRINOX（奥沙利铂+伊立替康+5-氟尿嘧啶/亚叶酸）三药方案和AG（白蛋白结合型紫杉醇+吉西他滨）两药方案，二线尚无标准治疗方案，CSCO指南推荐伊立替康脂质体联合氟尿嘧啶/亚叶酸钙。整体来看，目前胰腺癌仍存在大量未被满足的治疗需求，一是生存状态差，二是后续治疗匮乏。随着靶向治疗、免疫疗法以及细胞疗法的进展，近年来胰腺癌的治疗也取得一定的进展：（1）2005年11月，FDA批准EGFR 抑制剂厄洛替尼联合吉西他滨用于治疗局部晚期、不可切除或转移性胰腺癌；（2）2011年5月，FDA批准Afinitor（依维莫司）用于治疗进行性或转移性胰腺神经内分泌肿瘤不可手术移除；（3）2015年10月，FDA批准Onivyde（盐酸伊立替康脂质体注射液）与氟尿嘧啶和亚叶酸联用，用于治疗以吉西他滨为基础的治疗后疾病进展后的转移性胰腺腺癌患者；（4）2016年12月，FDA批准Sutent（舒尼替尼）用于治疗外科手术无法切除或已扩散到身体其他部位（转移）的进展性胰腺神经内分泌肿瘤；（5）2019年12月，FDA批准PARP抑制剂 Olaparib（奥拉帕尼）用于携带有害或疑似有害胚系BRCA突变（gBRCAm），至少16周一线含铂基础化疗无疾病进展成年转移性胰腺癌患者的维持治疗。而且，目前还有多款新药被开发用于治疗胰腺癌（详见下表），且有多款已进入3期临床。pamrevlumab是一款结缔组织生长因子（CTGF）抑制剂，曾被FDA授予治疗胰腺癌的孤儿药资格和快速通道资格认定，目前正在进行联合吉西他滨和白蛋白结合紫杉醇用于治疗无法切除的局部晚期胰腺癌的3期临床试验。NIS793是一款全人源抗转化生长因子β（TGF-β） IgG2单克隆抗体，曾被FDA授予联合标准护理化疗治疗胰腺癌的孤儿药资格。目前，该药联合化疗一线转移性胰腺癌的临床试验已进入3期，而且公司还在探索其联合抗PD-1药物spartalizumab（PDR001）的治疗潜力。Eryaspase由封装在供体来源的红细胞内的L-天冬酰胺酶组成，可作用于癌细胞改变的天冬酰胺和谷氨酰胺代谢。一项针对晚期胰腺癌患者的早期 IIb 期研究显示，eryaspase联合化疗可提高总生存期 (OS) 和无进展生存期 (PFS)。eryaspase联合化疗对比单独化疗作为晚期胰腺癌患者二线治疗的随机3期研究（Trybeca-1）结果。Zenocutuzumab是一款可以同时与HER2和HER3受体相结合的双特异性抗体，它可以阻止HER2和HER3形成二聚体，从而阻断神经调节蛋白的信号传导。2021年ASCO年会公布数据显示：在治疗NRG1融合阳性的胰腺癌患者时，zenocutuzumab达到42%（5/12）的确认总缓解率。SM-88是一种新型的联合疗法，由4种组分组成，其核心组分是一种功能失调的酪氨酸衍生物，作为蛋白质合成(包括粘液素)的错误构建模块，其他3种组分为西洛莫司、苯妥英和甲氧沙林，在亚治疗水平上用于改变患者或其肿瘤的生理机能，以补充和增强SM-88的活性。2019年88-Panc试验数据显示，与历史研究数据相比，SM-88显著提高了晚期胰腺癌患者的总生存期。然而，今年初TYME Technologies公布SM-88在转移性胰腺癌中相较标准护理化疗未能提高生存率。 Sotorasib是全球首款获批的针对KRAS G12C的靶向药，2021年5月被FDA批准用于治疗患有KRAS G12c突变的非小细胞肺癌。今年ASCO年会上该药治疗KRAS G12c突变胰腺癌的单臂1/2期临床试验CodeBreaK100结果显示：接受Sotorasib治疗胰腺癌患者的整体缓解率为21.1%，疾病控制率为84.2%，治疗的中位缓解持续时间为5.7个月，中位无进展生存期为4.0个月，中位总生存期为6.9个月。Adagrasib也是一款针对KRAS G12C突变体的特异性优化口服抑制剂，已公布的2期临床试验KRYSTAL-1结果显示，Adagrasib单药疗法在先前治疗过的胰腺导管腺癌显示出令人鼓舞的临床活性。具体数据为：在10例可评估的胰腺癌患者中，缓解率（RR）为50%，包括1例未确认的部分缓解（PR），疾病控制率（DCR）为100%，中位缓解持续时间（mDOR）为7.0个月，中位随访时间为8.1个月，中位无进展生存期（mPFS）为6.6个月。Onivyde，即伊立替康脂质体注射。2021年12月，Onivyde与NALIRIFOX化疗方案（包含5-氟尿嘧啶/亚叶酸钙、奥沙利铂）的组合疗法被FDA授予快速通道资格，用于以前未经治疗、无法切除的局部晚期和转移性胰腺导管腺癌患者。近来，益普生宣布Onivyde与NALIRIFOX化疗方案（包含5-氟尿嘧啶/亚叶酸钙、奥沙利铂）的组合疗法，在临床3期试验中达成主要终点：在与吉西他滨与白蛋白紫杉醇（nab-paclitaxel）组合疗法相比，此疗法能显著改善那些未曾接受过前期治疗的转移性胰腺导管腺癌（mPDAC）患者的总生存期。pelareorep是一款处于临床试验阶段的溶瘤病毒产品，是一种静脉注射的呼肠孤病毒，可诱导选择性肿瘤溶解并使“冷”肿瘤变“热”， 通过激活人体自身免疫系统，选择性地感染和摧毁肿瘤细胞，用于治疗多种实体瘤和血液恶性肿瘤。其联合PD-L1抑制剂和化疗一线治疗晚期/转移性胰腺导管腺癌的I/II期临床试验GOBLET结果显示：截止2022年7月28日，10例可评估疗效的患者中有7例患者获得了部分缓解（PR），2例患者病情稳定（SD）。客观缓解率（ORR）为70%，临床获益率（CBR）为90%。安全性方面，研究的组合未观察到安全信号。AB680是一种超强效、选择性小分子CD73抑制剂(CD73是肿瘤微环境中生成免疫抑制性腺苷的主要酶，能将单磷酸腺苷(AMP)转化为腺苷，从而在肿瘤微环境中形成免疫抑制。CD73高表达与多种肿瘤类型的预后显著较差相关，包括胰腺癌）。已公布的AB680联合nab-紫杉醇和吉西他滨（NP/Gem）以及zimberelimab（抗PD-1抗体）一线治疗转移性胰腺导管腺癌的开放标签、单臂1/1b期临床试验结果显示：19名入组的转移性胰腺癌患者中17例可评估，其中16例在疗效评估时间点仍在接受治疗。具体数据为：17名患者中，15名（88%）患者病灶出现缩小。ORR为41%（7/17），其中包括一名CR的患者。在接受药物治疗超过16周的患者中，组合疗法达到85%（11/13）的疾病控制率。KN046是康宁杰瑞自主研发的一款PD-L1/CTLA-4双特异性抗体，已公布的2期临床研究结果显示KN046联合白蛋白紫杉醇/吉西他滨一线治疗晚期胰腺导管腺癌的ORR相较AG方案的历史ORR提高了一倍以上，且耐受性良好。CEND-1是一种经过临床前和早期临床验证的肿瘤穿透肽，通过激活肿瘤特异性转运机制，使抗癌药物蓄积并渗透到肿瘤中而非正常组织中。研究发现，当CEND-1与不同抗肿瘤药物联合用药（不需要结合形成新的化学实体）时，可增加药物的肿瘤组织渗透性，增强药物向实体瘤组织的递送和肿瘤组织药物浓度，而不影响非肿瘤组织药物浓度，从而提高抗肿瘤药物抗癌效果。已公布的在澳大利亚完成的CEND-1治疗转移性胰腺癌患者的1期临床试验结果显示：CEND-1与吉西他滨和白蛋白紫杉醇联用，在治疗转移性胰腺癌患者时达到59%的总缓解率，其中一名患者达到完全缓解，16名患者达到部分缓解，10名患者病情稳定，疾病控制率达到83%。SHR-1701是抗PD-L1/TGF-βRII双功能融合蛋白，可以促进效应性T细胞的活化，同时还可有效改善肿瘤微环境中的免疫调节作用，最终有效促进免疫系统对于肿瘤细胞的杀伤。然而，胰腺癌的相关研究进展并不顺利，免疫疗法中PD-1单抗durvalumab联合CTLA-4单抗tremelimumab，以及信迪利单抗联合改良FOLFIRINOX方案(mFFX)治疗转移性胰腺癌的临床试验均未达到主要终点。而胰腺癌免疫治疗效果不尽如人意和其特殊的免疫抑制微环境有很大关系。胰腺癌纤维间质的形成、髓系来源免疫抑制细胞的增多、细胞浸润功能的减退、物理屏障和化学屏障的作用，以及细胞因子分泌的相对不足，都导致胰腺癌成为冷肿瘤，这使免疫治疗效果不理想。不过双抗、溶瘤病毒、KRAS G12C抑制剂等在胰腺癌治疗领域还值得期待，期盼未来科学家们可以早日攻克“癌王”。企业推荐智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPhI制药在线▼点击阅读原文，进入智药研习社~

-- Combined Company to Trade on Nasdaq Under Ticker “SYRS” ---- Syros Announces 1-for-10 Reverse Stock Split of Common Stock -- CAMBRIDGE, Mass. and BEDMINSTER, N.J., Sept. 15, 2022 (GLOBE NEWSWIRE) -- Syros Pharmaceuticals, Inc. (NASDAQ:SYRS), a leader in the development of medicines that control the expression of genes, and Tyme Technologies, Inc. (NASDAQ:TYME) today announced the results of the special meetings of the stockholders of Syros and TYME, respectively, each held on September 15, 2022. At TYME’s special meeting, TYME’s stockholders voted in favor of all proposals, including the proposal to adopt the agreement and plan of merger, dated July 3, 2022 (the “Merger Agreement”), pursuant to which a direct, wholly owned subsidiary of Syros will merge with and into TYME, with TYME surviving as a wholly owned subsidiary of Syros (the “Merger”). At Syros’ special meeting, Syros’ stockholders also voted in favor of all proposals, including the proposal to approve the issuance of shares of Syros’ common stock to holders of TYME’s common stock in connection with the Merger and to certain of Syros’ investors in connection with a concurrent private investment in public equity (“PIPE”) financing. The closings of the Merger and the PIPE financing are anticipated to take place on or around Friday, September 16, 2022. Following the closing of the Merger, the combined company will trade on The Nasdaq Global Select Market under the ticker symbol “SYRS,” and will be led by Syros’ existing management team, including Nancy Simonian, M.D., Chief Executive Officer of Syros, and will remain focused on advancing Syros’ pipeline of small molecule medicines for the treatment of cancer. In addition, Syros today announced that it will effect a 1-for-10 reverse stock split of its common stock that will be effective on Friday, September 16, 2022, prior to the closings of the Merger and the PIPE financing. Syros’ common stock will begin trading on Nasdaq on a split-adjusted basis when the market opens on Monday, September 19, 2022. The new CUSIP number for Syros’ common stock following the reverse stock split is 87184Q206. On September 15, 2022, the holders of a majority of Syros’ outstanding shares of common stock also approved the reverse stock split and gave Syros’ board of directors discretionary authority to select a ratio for the split ranging from 1-for-5 to 1-for-15. Syros’ board of directors approved the reverse stock split at a ratio of 1-for-10 on September 15, 2022. The reverse stock split affects all issued and outstanding shares of Syros common stock, as well as the number of authorized shares of Syros common stock and the number of shares of common stock available for issuance under Syros’ equity incentive plans. The reverse stock split will reduce the number of shares of the Syros issued and outstanding common stock from approximately 63 million to approximately 6.3 million (which numbers do not give effect to the shares of Syros common stock to be issued in connection with the Merger and the PIPE financing). In addition, the reverse stock split will effect a reduction in the number of shares of common stock issuable upon the exercise of stock options and warrants and upon the vesting of restricted stock units outstanding immediately prior to the reverse stock split, with a proportional increase in the respective exercise prices. The reverse stock split will proportionately reduce the number of authorized shares of Syros’ common stock from 700 million shares (which is the number of authorized shares that will be outstanding immediately prior to the reverse stock split, in connection with Syros’ receipt of the approval of its stockholders to increase the number of authorized shares from 200 million to 700 million) to 70 million shares. The reverse stock split will not change the par value of the common stock or the authorized number of shares of preferred stock of Syros. The reverse stock split will affect all holders of common stock uniformly and (before giving effect to the shares of Syros common stock to be issued in connection with the Merger and the PIPE financing) will not alter any stockholder’s percentage ownership interest in Syros, except to the extent that the reverse stock split would result in a stockholder owning a fractional share. No fractional shares of common stock will be issued in connection with the reverse stock split; stockholders who otherwise would be entitled to a fractional share of common stock will be entitled to receive a proportional cash payment. Syros’ transfer agent, Computershare, is acting as the exchange agent for the reverse stock split. For those stockholders holding physical stock certificates, Computershare will send instructions for exchanging those certificates for shares held in book-entry form representing the post-split number of shares. Stockholders holding their shares in book-entry form or in brokerage accounts need not take any action in connection with the reverse stock split. Beneficial holders are encouraged to contact their bank, broker or custodian with any procedural questions. About Syros Pharmaceuticals Syros is redefining the power of small molecules to control the expression of genes. Based on its unique ability to elucidate regulatory regions of the genome, Syros aims to develop medicines that provide a profound benefit for patients with diseases that have eluded other genomics-based approaches. Syros is advancing a robust clinical-stage pipeline, including: tamibarotene, a first-in-class oral selective RARα agonist in RARA-positive patients with higher-risk myelodysplastic syndrome and acute myeloid leukemia; SY-2101, a novel oral form of arsenic trioxide in patients with acute promyelocytic leukemia; and SY-5609, a highly selective and potent oral CDK7 inhibitor in patients with select solid tumors. Syros also has multiple preclinical and discovery programs in oncology and monogenic diseases. For more information, visit www.syros.com and follow us on Twitter (@SyrosPharma) and LinkedIn. About Tyme Technologies, Inc. TYME is an emerging biotechnology company developing cancer metabolism-based therapies (CMBTs™) that are intended to be effective across a broad range of solid tumors and hematologic cancers, while also maintaining patients’ quality of life through relatively low toxicity profiles. Unlike targeted therapies that attempt to regulate specific mutations within cancer, TYME’s therapeutic approach is designed to take advantage of a cancer cell’s innate metabolic weaknesses to cause cancer cell death. TYME is currently focused on developing its novel compound, SM-88 and its preclinical pipeline of novel CMBT™ programs. TYME believes that early clinical results demonstrated by SM-88 in multiple advanced cancers, including prostate, sarcomas and breast, reinforce the potential of its emerging CMBT™ pipeline. Cautionary Note Regarding Forward-Looking Statements This press release contains forward-looking statements (including within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and Section 27A of the Securities Act of 1933, as amended (the “Securities Act”) concerning Syros, TYME, the proposed transactions and other matters, such as Syros’ clinical development plans, including with respect to tamibarotene, SY-2101 and SY-5609 and Syros’ ability to deliver benefit to patients and value to stockholders. These statements may discuss goals, intentions and expectations as to future plans, trends, events, results of operations or financial condition, or otherwise, based on current beliefs of the management of Syros and TYME, as well as assumptions made by, and information currently available to, management of Syros and TYME. Forward-looking statements generally include statements that are predictive in nature and depend upon or refer to future events or conditions, and include words such as “may,” “will,” “should,” “would,” “expect,” “anticipate,” “plan,” “likely,” “believe,” “estimate,” “project,” “intend,” and other similar expressions. Statements that are not historical facts are forward-looking statements. Forward-looking statements are based on current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation, Syros’ ability to: advance the development of its programs, including tamibarotene, SY-2101 and SY-5609, under the timelines it projects in current and future clinical trials; demonstrate in any current and future clinical trials the requisite safety, efficacy and combinability of its drug candidates; sustain the response rates and durability of response seen to date with its drug candidates; successfully develop a companion diagnostic test to identify patients with the RARA biomarker; obtain and maintain patent protection for its drug candidates and the freedom to operate under third party intellectual property; obtain and maintain necessary regulatory approvals; identify, enter into and maintain collaboration agreements with third parties; manage competition; manage expenses; raise the substantial additional capital needed to achieve its business objectives; attract and retain qualified personnel; and successfully execute on its business strategies. Additional factors that could cause actual results to differ materially from those contained in any forward-looking statement include, without limitation, the risk that the conditions to the closing of the proposed transactions are not satisfied, including the failure to complete the PIPE financing in a timely manner or at all; uncertainties as to the timing of the consummation of the transactions and the ability of each of Syros and TYME to consummate the transaction, including the PIPE financing; risks related to TYME’s continued listing on the Nasdaq Stock Market until closing of the proposed transactions; risks related to Syros’ and TYME’s ability to correctly estimate their respective operating expenses and expenses associated with the transactions, as well as uncertainties regarding the impact any delay in the closing would have on the anticipated cash resources of the combined company upon closing and other events and unanticipated spending and costs that could reduce the combined company’s cash resources; the ability of Syros or TYME to protect their respective intellectual property rights; competitive responses to the transaction; unexpected costs, charges or expenses resulting from the transaction; potential adverse reactions or changes to business relationships resulting from the announcement or completion of the transaction; and legislative, regulatory, political and economic developments. The foregoing review of important factors that could cause actual events to differ from expectations should not be construed as exhaustive and should be read in conjunction with statements that are included herein and elsewhere, including the risk factors included in the Registration Statement on Form S-4 (the “Registration Statement”) filed by Syros with the Securities and Exchange Commission (the “SEC”), Syros’ Annual Report on Form 10-K for the year ended December 31, 2021, Syros’ Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, TYME’s Annual Report on Form 10-K for the year ended March 31, 2022, and TYME’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, each of which is on file with the SEC. In addition, the extent to which the COVID-19 pandemic continues to impact the proposed transactions will depend on future developments, which are highly uncertain and cannot be predicted with confidence, including the duration and severity of the pandemic, additional or modified government actions, and the actions that may be required to contain the virus or treat its impact. Syros and TYME can give no assurance that the conditions to the transactions will be satisfied. Except as required by applicable law, Syros and TYME undertake no obligation to revise or update any forward-looking statement, or to make any other forward-looking statements, whether as a result of new information, future events or otherwise. This press release contains hyperlinks to information that is not deemed to be incorporated by reference in this press release. No Offer or Solicitation This press release is not a proxy statement or solicitation of a proxy, consent or authorization with respect to any securities or in respect of the proposed business combination and shall not constitute an offer to sell or a solicitation of an offer to buy any securities nor shall there be any sale of securities in any state or jurisdiction in which such offer, solicitation, or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. No offer of securities shall be made except by means of a prospectus meeting the requirements of the Securities Act. Syros’ Media Contact: Brittany Leigh, Ph.D.LifeSci Communications, LLC+1-813-767-7801bleigh@lifescicomms.com Syros’ Investor Contact: Hannah DeresiewiczStern Investor Relations, Inc.212-362-1200hannah.deresiewicz@sternir.com Tyme’s Investor Contactinvestorrelations@tymeinc.com