Vorinostat

Hemophilia Program: Ongoing registrational PRESent-2 and PRESent-3 studies of SerpinPC for the treatment of hemophilia B; PRESent-2 advancing toward interim analysis planned in 2024 Orexin Agonist Program: Clinical proof-of-concept data for ORX750 in sleep-deprived healthy volunteers planned in 2024 LockBody® Technology Platform: Ongoing Phase 1/2a study of LB101 (PD-L1xCD47)for the treatment of solid tumors BOSTON and LONDON, March 28, 2024 (GLOBE NEWSWIRE) -- Centessa Pharmaceuticals plc (Nasdaq: CNTA), a clinical-stage pharmaceutical company, today reported recent business highlights and financial results for the fourth quarter and full-year ended December 31, 2023. “This is an exciting and pivotal time for Centessa,” said Saurabh Saha MD PhD, Chief Executive Officer of Centessa. “We are laser focused on executing the PRESent registrational studies for SerpinPC, a potential first-in-class subcutaneously administered therapy with a differentiated safety pro individuals with hemophilia B, and advancing our orexin receptor 2 (OX2R) agonist development program into the clinic for the treatment of narcolepsy and other sleep-wake disorders.” Dr. Saha continued, “SerpinPC’s novel mechanism of action is designed to prevent or reduce bleeding in persons with hemophilia without depleting natural anticoagulants that help prevent blood clots. The most recent clinical data from our ongoing Phase 2a study showed that an additional 52-weeks of continuous treatment with SerpinPC reduced the median all-bleed ABR by 96% relative to baseline, and no thrombosis has been observed across the study to date. Within the PRESent registrational studies for SerpinPC, we are looking to replicate this safety pro meaningfully reduce bleeding rates for subjects with hemophilia B, with or without inhibitors. We look forward to confirming a dose and advancing to Part 2 of the PRESent-2 study this year.” “We are very excited with progress within our OX2R agonist development program, and more specifically, ORX750, an orally administered, highly potent and selective OX2R agonist,” said Dr. Saha. “In late 2023, we shared preclinical data that we believe support ORX750’s potential to be a best-in-class oral OX2R agonist for the treatment of narcolepsy and other sleep-wake disorders. We remain on track with our goal to share clinical proof-of-concept data for ORX750 in sleep-deprived healthy volunteers this year.” “In parallel, we continue to evaluate our proprietary LockBody technology platform in a first-in-human clinical study of LB101, a conditionally tetravalent PD-L1xCD47 bispecific monoclonal antibody designed to selectively drive CD47 into the tumor microenvironment while avoiding systemic toxicity, in solid tumors. We look to this study to provide valuable insights regarding the safety and tolerability of LB101, as well as the performance of our LockBody platform in a clinical setting.” Recent Highlights In December 2023 and February 2024, the Company presented data from an additional 52-weeks of continuous treatment from the third year (Part 5) of the ongoing Phase 2a study of SerpinPC, an investigational subcutaneously administered novel inhibitor of activated protein C (APC) for the treatment of hemophilia, during presentations at the American Society of Hematology (ASH) Annual Meeting and the 17th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD). Part 5 data from the Phase 2a study showed a continued favorable safety and tolerability pro SerpinPC, as well as sustained long-term efficacy results, as measured by a 96% reduction in the median all-bleed annualized bleeding rate (ABR) from the prospective baseline measured during the pre-exposure observation period. To date, there have been no thromboembolic events and no treatment-related sustained elevations of D-dimer observed throughout the Phase 2a study. In October 2023, the Company announced the dosing of the first subject in its registrational PRESent-3 clinical study of SerpinPC for the treatment of hemophilia B with inhibitors. The Company initiated dosing in its registrational PRESent-2 clinical study of SerpinPC for the treatment of hemophilia B without inhibitors in July 2023. In October 2023, the Company announced preclinical data from in vivo and in vitro studies of its investigational, novel OX2R agonist, ORX750, that we believe support a potential best-in-class pro the treatment of narcolepsy and other sleep-wake disorders. Anticipated Upcoming Program Milestones Hemophilia Program - The registrational PRESent-2 (hemophilia B without inhibitors) and PRESent-3 (hemophilia B with inhibitors) studies of SerpinPC are ongoing. For PRESent-2, the Company plans to confirm a dose and advance to Part 2 of the study based on a review of Part 1 (dose justification) data in 2024 (interim analysis). The primary endpoint of the PRESent-2 study is the rate of treated bleeds (expressed as ABR) during the first 24 weeks of treatment with SerpinPC (Part 2) compared to the observation period. The Company plans to share Part 1 data at a medical conference in late 2024 or early 2025. Orexin Agonist Program - Upon Investigational New Drug (“IND”) clearance, the Company plans to rapidly advance ORX750 into clinical development with the goal of sharing clinical proof-of-concept data in sleep-deprived healthy volunteers in 2024. LockBody Technology Platform - The Phase 1/2a first-in-human clinical study of LB101 (PD-L1xCD47 LockBody) is ongoing. Where applicable, the Company plans to provide updates on preclinical programs including follow-up orexin agonists and LB206, a PD-L1xCD3 LockBody, when they advance toward clinical studies. Fourth Quarter and Full-Year 2023 Financial Results Cash, Cash Equivalents and Short-term Investments: $256.5 million as of December 31, 2023, which includes approximately $6.2 million in net proceeds through ATM sales in the fourth quarter ended December 31, 2023. In addition, the Company received approximately $9.7 million in net proceeds through ATM sales in January 2024. The Company expects its cash, cash equivalents and short-term investments will fund operations into 2026, without drawing on the remaining available tranches under the Oberland credit facility. Research & Development Expenses: $29.7 million for the fourth quarter ended December 31, 2023, compared to $27.8 million for the fourth quarter ended December 31, 2022, and $124.4 million for the full-year 2023 compared to $155.1 million for the full-year 2022. General & Administrative Expenses: $12.3 million for the fourth quarter ended December 31, 2023, compared to $13.8 million the fourth quarter ended December 31, 2022, and $53.7 million for the full-year 2023 compared to $55.2 million for the full-year 2022. Net Loss Attributable to Ordinary Shareholders: $36.8 million for the fourth quarter ended December 31, 2023, compared to $43.2 million for the fourth quarter ended December 31, 2022, and $151.1 million for the full-year 2023 compared to $216.2 million for the full-year 2022. About Centessa Pharmaceuticals Centessa Pharmaceuticals plc is a clinical-stage pharmaceutical company that aims to discover and develop medicines that are transformational for patients. Our most advanced programs include a hemophilia program, an orexin agonist program for the treatment of narcolepsy and other sleep-wake disorders and an immuno-oncology program focused on our LockBody® technology platform. We operate with the conviction that each of our programs has the potential to change the current treatment paradigm and establish a new standard of care. For more information, visit , which does not form part of this release. About SerpinPC SerpinPC is an investigational subcutaneously administered novel inhibitor of APC being developed as a potential treatment for hemophilia, regardless of severity or inhibitor status, and which may also be developed to prevent bleeding associated with other bleeding disorders. The registrational program for SerpinPC in hemophilia B includes a set of clinical studies with multiple components. PRESent-5 is an observational feeder study to collect prospective observational data for minimum defined periods before switching to dosing subjects in the interventional studies. The interventional studies include PRESent-2 (moderately severe to severe hemophilia B without inhibitors, and severe hemophilia A with or without inhibitors) and PRESent-3 (hemophilia B with inhibitors). Additional information on the trials can be accessed at (NCT05605678, NCT05789524, NCT05789537). The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to SerpinPC for the treatment of hemophilia B, with or without inhibitors. SerpinPC has not been approved by the FDA or any other regulatory authority for any use. About ORX750 ORX750 is an investigational, orally administered, highly potent and selective orexin receptor 2 (OX2R) agonist designed to directly target the underlying pathophysiology of orexin neuron loss in narcolepsy type 1 (NT1). ORX750 has been shown in preclinical studies to potently activate the OX2R with an in vitro EC50 of 0.11 nM and 9,800-fold selectivity over the human orexin receptor (hOX1R). ORX750 is Centessa’s first orexin product candidate being developed for the treatment of narcolepsy with potential expansion into other sleep-wake disorders. ORX750 has not been approved by the FDA or any other regulatory authority. About the LockBody Technology Platform and LB101 Centessa’s proprietary LockBody technology platform aims to redefine immuno-oncology treatment for patients with cancer. LockBody drug candidates are designed to selectively drive potent effector function activity, such as CD47 or CD3, to the tumor micro-environment (TME) while avoiding systemic toxicity. The first LockBody candidate is LB101, a conditionally tetravalent PD-L1xCD47 bispecific monoclonal antibody which has two anti-CD47 domains blocked by two anti-PD-L1 domains, with proprietary human IgG-derived hinges linking the anti-CD47 and anti-PD-L1 domains. The cell-killing mechanism of action, CD47, is designed to be blocked by the PD-L1 tumor targeting domain until the IgG-derived hinges are naturally degraded in the TME, thus unlocking and activating the CD47 effector function activity in the tumor. LB101 is in a Phase 1/2a clinical trial. Additional information on the trial can be accessed at (NCT05821777). LB101 is an investigational agent that has not been approved by the FDA or any other regulatory authority. Forward Looking Statements This press release contains forward-looking statements. These statements may be identified by words such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” “aim,” “seek,” and variations of these words or similar expressions that are intended to identify forward-looking statements. Any such statements in this press release that are not statements of historical fact may be deemed to be forward-looking statements, including statements related to the Company’s ability to discover and develop transformational medicines for patients; its expectations for executing on the Company's pipeline; its expectations on its anticipated cash runway; the timing of commencement of new studies or clinical trials or clinical and preclinical data related to SerpinPC, LB101, LB206, other LockBody candidates, the LockBody technology platform, ORX750 and other orexin agonist molecules; its ability to identify, screen, recruit and maintain a sufficient number of or any subjects in its existing and anticipated studies or clinical trials including PRESent-5, the observational feeder study, PRESent-2 and PRESent-3 and studies or trials of LB101, LB206, and any other LockBody candidates, ORX750 and other orexin agonist molecules and its expectations on executing its research and clinical development plans and the timing thereof; the Company’s ability to differentiate SerpinPC, LB101, LB206, other LockBody candidates, ORX750 and other orexin agonist molecules from other treatment options; the development, design and therapeutic potential of SerpinPC, LB101, LB206, other LockBody candidates, the LockBody technology platform, ORX750 and other orexin agonist molecules; and regulatory matters, including the timing and likelihood of success of obtaining regulatory clearance, obtaining authorizations to initiate or continue clinical trials. Any forward-looking statements in this press release are based on our current expectations, estimates, assumptions and projections only as of the date of this release and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, risks related to the safety and tolerability pro our product candidates; our ability to identify, screen and recruit a sufficient number of or any subjects in our existing and anticipated new studies or clinical trials including PRESent-2, PRESent-3, PRESent-5, and studies or trials of LB101 or within anticipated timelines; our ability to execute IND-enabling activities in a timely manner or at all, including with respect to ORX750 and LB206; our ability to protect and maintain our intellectual property position; business (including commercial viability), regulatory, economic and competitive risks, uncertainties, contingencies and assumptions about the Company; risks inherent in developing product candidates and technologies; future results from our ongoing and planned clinical trials; our ability to obtain adequate financing, including through our financing facility with Oberland, to fund our planned clinical trials and other expenses; trends in the industry; the legal and regulatory framework for the industry, including the receipt and maintenance of clearances to conduct or continue clinical testing; our operating costs and use of cash, including cash runway, cost of development activities and conducting clinical trials, future expenditures risks; the risk that any one or more of our product candidates will not be successfully developed and/or commercialized; the risk that the historical results of preclinical studies or clinical studies will not be predictive of future results in ongoing or future studies; economic risks to the United States and United Kingdom banking systems; and geo-political risks such as the Russia-Ukraine war or the Israeli-Palestinian conflict. These and other risks concerning our programs and operations are described in additional detail in our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and our other reports, which are on the U.S. Securities and Exchange Commission (SEC). We explicitly disclaim any obligation to update any forward-looking statements except to the extent required by law. Contact: Kristen K. Sheppard, Esq. SVP of Investor Relations investors@centessa.com Centessa Pharmaceuticals plc Consolidated Statements of Operations and Comprehensive Loss (unaudited) (amounts in thousands except share and per share data) Quarter Ended December 31, 2023 Quarter Ended December 31, 2022 Year Ended December 31, 2023 Year Ended December 31, 2022 License and other revenue $ 6,853 $ — $ 6,853 $ — Operating expenses: Research and development 29,716 27,835 124,405 155,083 General and administrative 12,315 13,768 53,731 55,200 Change in fair value of contingent value rights — — — 1,980 Loss from operations (35,178 ) (41,603 ) (171,283 ) (212,263 ) Interest income 2,933 39 10,476 244 Interest expense (2,570 ) (2,203 ) (9,906 ) (7,277 ) Other (expense) income, net (878 ) (70 ) (5,428 ) 2,342 Loss before income taxes (35,693 ) (43,837 ) (176,141 ) (216,954 ) Income tax (benefit) expense 1,144 (664 ) (25,056 ) (747 ) Net loss (36,837 ) (43,173 ) (151,085 ) (216,207 ) Other comprehensive income (loss): Foreign currency translation adjustment 459 198 1,700 (2,185 ) Unrealized gain on available for sale securities, net of tax 255 — 1,290 — Total comprehensive loss $ (36,123 ) $ (42,975 ) $ (148,095 ) $ (218,392 ) Net loss per ordinary share - basic and diluted $ (0.38 ) $ (0.45 ) $ (1.57 ) $ (2.31 ) Weighted average ordinary shares outstanding - basic and diluted 97,923,585 94,603,860 96,177,578 93,400,513 Centessa Pharmaceuticals plc Condensed Consolidated Balance Sheets (unaudited) (amounts in thousands) December 31, 2023 December 31, 2022 Total assets: Cash and cash equivalents $ 128,030 $ 393,644 Short-term investments 128,519 — Other assets 103,697 50,663 Total assets $ 360,246 $ 444,307 Total liabilities Other liabilities $ 48,302 $ 38,338 Long term debt 75,700 69,800 Total liabilities 124,002 108,138 Total shareholders’ equity 236,244 336,169 Total liabilities and shareholders' equity $ 360,246 $ 444,307

本文为转化医学网原创，转载请注明出处 作者：Rainbow 导读： 目前用于乳腺癌的传统治疗方法，包括免疫检查点阻断，在某些癌症中表现出有限的效果，特别是三阴性乳腺癌。表观遗传改变，特别是DNMT和HDAC的改变，与乳腺癌的发病机制有关。 3月15日，深圳大学研究团队在期刊《Cell Death Discovery》上在线发表题为“Dual inhibitors of DNMT and HDAC induce viral mimicry to induce antitumour immunity in breast cancer”的研究论文，研究结果表明， 15a作为一种新型有效的DNMTs和HDACs双重抑制剂具有巨大的潜力，并提高了乳腺癌体内模型的生存率。这种效应至少部分归因于病毒模拟反应的诱导。因此，15a代表了一种有前景的候选药物，用于安全有效地靶向癌症，从而为治疗各种预后不良的人类肿瘤开辟了途径。 https://www.nature.com/articles/s41420-024-01895-7 研究背景 01 尽管乳腺癌的早期检测和治疗取得了显著进展，但该疾病的异质性和侵袭性使得检测和治疗具有挑战性。因此，乳腺癌仍然是女性癌症相关死亡的主要原因，仅次于肺癌。免疫检查点阻断（ICB）疗法的采用虽然在治疗黑色素瘤和肺癌方面已经取得了早期成功，但进展相对缓慢。 因此，开发创新策略和治疗方法以提高患者的存活率至关重要。 在2022年最近发现的肿瘤特征中，非突变表观遗传重编程已经成为一种新颖特征。癌症是一种复杂的疾病，涉及遗传和表观遗传改变。表观遗传机制对癌症生物学的多个方面产生重要影响，包括促进原发肿瘤生长和侵袭，以及调节肿瘤微环境内的免疫应答。这些机制涉及DNA甲基化和组蛋白修饰之间的复杂相互作用。 在参与表观遗传调控的各类酶中，DNA甲基转移酶（DNMT）和组蛋白去乙酰化酶（HDAC）尤为重要。 事实上，已经开发出靶向药物，如DNMT抑制剂地西他滨和HDAC抑制剂伏立诺他（SAHA），以特异性靶向这些酶。 研究发现 02 研究人员证明了DNMT 和 HDAC 在乳腺癌中过表达和正相关。DNMT和HDAC抑制剂的联合应用显示出协同的抗肿瘤效果，而研究人员先前设计的双重DNMT和HDAC抑制剂（称为DNMT/HDACi）15a在体内外能够有效抑制乳腺癌细胞的增殖、迁移和侵袭，并诱导凋亡。机制上，15a通过促进乳腺癌细胞内源逆转录病毒元件的表达诱导病毒模拟反应，从而增加细胞内双链RNA水平以激活RIG-I-MAVS通路。这进而促进干扰素和趋化因子的产生，并增强干扰素刺激基因和PD-L1的表达。15a与抗PD-L1抗体的联合在体内具有累加效应。 这些发现表明，这种DNMT/HDACi具有免疫调节功能，并增强了免疫检查点阻断治疗的有效性。 研究结论 03 综上所述，研究结果表明， 15a作为一种新型有效的DNMTs和HDACs双重抑制剂具有巨大的潜力，并提高了乳腺癌体内模型的生存率。这种效应至少部分归因于病毒模拟反应的诱导。因此，15a代表了一种有前景的候选药物，用于安全有效地靶向癌症，从而为治疗各种预后不良的人类肿瘤开辟了途径。 参考资料： https://www.nature.com/articles/s41420-024-01895-7 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情