Ritonavir

NEWTOWN, Pa., June 03, 2025 (GLOBE NEWSWIRE) -- Traws Pharma, Inc. (NASDAQ: TRAW) (“Traws Pharma”, “Traws” or “the Company”), a clinical-stage biopharmaceutical company developing novel therapies to target critical threats to human health from respiratory viral diseases, today announced the publication of key clinical efficacy data for rigosertib, a legacy Traws Pharma oncology asset for which development and commercialization partners are being actively sought, in patients with RDEB SCC. The paper, published in the British Journal of Dermatology1, details the first clinical trial of any experimental cancer therapeutic in this rare and complicated monogenic disease. The results indicated an overall response rate of 80%, with complete responses in 50% of evaluable patients. “These data indicate that rigosertib is a potential treatment for cutaneous SCC in RDEB patients, where there is a substantial unmet need and no approved therapies. The aggressive course of this disease is inadequately addressed by current treatment regimens, which produce limited response rates of mostly short duration,” said Victor Moyo, MD, Chief Medical Officer Oncology, Traws Pharma. “We are excited to report the compelling efficacy and tolerability profile of rigosertib in this devastating, difficult to treat disease, and thank the patients, sponsors and investigators for their commitment to this program,” commented Iain Dukes, MA, DPhil, Interim CEO, Traws Pharma. “Rigosertib is available for further development and commercialization, and we are committed to finding an appropriate partner to advance this important medicine to approval.” About RDEB-associated SCC RDEB is caused by insufficient expression of type VII collagen, which is responsible for anchoring the skin’s inner layer to its outer layer. This leads to extreme skin fragility as well as chronic blistering and wound formation with recurrent infections in RDEB patients, many of whom go on to develop metastatic squamous cell carcinoma driven by overexpression of polo-like kinase 1 (PLK-1). RDEB-associated SCC tumors show a highly aggressive and early metastasizing course that makes them the primary cause of death for these patients, with a cumulative risk of death of 70% and 78.7% by ages 45 and 55, respectively2,3. RDEB-associated SCC can appear in pediatric patients or in young adults. Currently available treatments such as targeted therapies and conventional chemo- and/or radiotherapy have demonstrated limited response rates and poor durability in RDEB-associated SCC2,4. Abbreviations: RDEB SCC, Recessive Dystrophic Epidermolysis Bullosa Associated Locally Advanced or Metastatic Squamous Cell Carcinoma References Martin Laimer, Andrew P South, Elisabeth Mayr, Sophie Kitzmueller, Lauren Banner, Michael Alexander, Linda Hosler, Henry Yang, Matthew Parris, Meena Arora, Georg Zimmermann, Gregor Schweighofer-Zwink, Johann W Bauer, Neda Nikbakht, Efficacy and Safety of Rigosertib in Patients with Recessive Dystrophic Epidermolysis Bullosa Associated Advanced/Metastatic Cutaneous Squamous Cell Carcinoma, British Journal of Dermatology, 2025;, ljaf205, https://doi.org/10.1093/bjd/ljaf205Mellerio et al. Br J Dermatol. 2016 Jan; 174(1):56-67. doi: 10.1111/bjd.14104.Fine et al. J Am Acad Dermatol. 2009 Feb; 60(2):203-11. doi: 10.1016/j.jaad.2008.09.035.Stratigos et al. Eur J Cancer. 2020 Mar;128:83-102. doi: 10.1016/j.ejca.2020.01.008. About Rigosertib Rigosertib is a small molecule kinase inhibitor (including PLK-1). The compound is being evaluated in a series of investigator sponsored studies including as a monotherapy for potential use in advanced squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa (RDEB-associated SCC) (NCT03786237, NCT04177498), using both oral and IV formulations. Rigosertib has also been evaluated in combination with other agents, including checkpoint inhibitors, for solid tumors including non-small cell lung cancer, and metastatic melanoma. About Traws Pharma, Inc. Traws Pharma is a clinical stage biopharmaceutical company dedicated to developing novel therapies to target critical threats to human health in respiratory viral diseases. Traws integrates antiviral drug development, medical intelligence and regulatory strategy to meet real world challenges in the treatment of viral diseases. We are advancing novel investigational oral small molecule antiviral agents that have potent activity against difficult to treat or resistant virus strains that threaten human health: bird flu and seasonal influenza, and COVID-19/Long COVID. Tivoxavir marboxil is in development as a single dose treatment for bird flu and seasonal influenza, targeting the influenza cap-dependent endonuclease (CEN). Ratutrelvir is in development as a ritonavir-independent COVID treatment, targeting the Main protease (Mpro or 3CL protease). Traws is actively seeking development and commercialization partners for its legacy clinical oncology programs, rigosertib and narazaciclib. More details can be found on Traws’ website at https://www.ir.trawspharma.com/partnering. Follow our progress on our website or on LinkedIn. Forward-Looking Statements Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995, and involve risks and uncertainties including statements regarding the Company, its business and product candidates, including the potential opportunity, benefits and the regulatory plans for its rigosertib oncology program. The Company has attempted to identify forward-looking statements by terminology including “believes”, “estimates”, “anticipates”, “expects”, “plans”, “intends”, “may”, “could”, “might”, “will”, “should”, “preliminary”, “encouraging”, “approximately” or other words that convey uncertainty of future events or outcomes. Although Traws believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward looking statements. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including Traws’ ability to identify and enter into development and/or commercialization agreements with potential partners for its legacy rigosertib oncology program, the success and timing of Traws’ clinical trials, the efficacy of rigosertib as a treatment for cutaneous SCC in RDEB patients, market conditions, regulatory requirements, changes in government regulation, and those discussed under the heading “Risk Factors” in Traws’ filings with the U.S. Securities and Exchange Commission (SEC). Any forward-looking statements contained in this release speak only as of its date. Traws undertakes no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events, except to the extent required by law. Traws Pharma ContactNora BrennanTraws Pharma, Inc.nbrennan@trawspharma.com www.trawspharma.com Investor Contact:Bruce Mackle LifeSci Advisors, LLC646-889-1200bmackle@lifesciadvisors.com

氘代药物是把药物分子上特定位点的氢原子用氘原子替代所获得的药物，其中应用最广泛的是将碳-氢键替换成为碳-氘键。通过替换，可以改善药物的药代动力学和/或毒性。2017 年4月，美国食品药品监督管理局（FDA）批准了全球首个氘代药物-Auspex公司的氘代丁苯那嗪片（Deuterabenazine，安泰坦）上市，用于罕见的常染色体显性遗传病亨廷顿舞蹈病。2022年，FDA批准了另一款全新氘代药物Deucravacitinib，该药物被广泛应用于治疗多种自身免疫性疾病，包括经典型干燥症候群、类风湿性关节炎和牛皮癣等。本篇文章总结了氘代药物研究进展以及在开发过程中面临的挑战。01氘代动力学的同位素（DKIE）效应药物化学家使用各种方法改进候选化合物的结构，以期提高候选化合物的疗效和安全性。其中，用氘取代氢可以说是可最小的化学结构变化，但对候选化合物的特性会产生深远的影响。最初，氘代药物仅仅被认为可以提高候选化合物的代谢稳定性，随着研究的深入，这种修饰的效果可以远远超出简单的药代动力学（PK）改进，对药物的疗效和安全性产生重大影响。氢是宇宙中最丰富的元素，存在3种同位素：氢（1H，简称H，有一个质子和一个电子，丰度99.9844%），氘（2H，简称D，1个中子，丰度0.0156%）和氚（3H，简称T，2个中子，痕量）；如图1所示。T是一种放射性同位素，具有较长的半衰期（t½），但D稳定性更好。随着超灵敏质谱技术的出现，D广泛应用于生物医学领域。D是由大爆炸期间的核聚变产生的，1932年，哈罗德·尤里在1932年首次发现并命名。H与D有非常相似的物理化学性质，D具有较小的摩尔体积（0.140cm3/mol−1/原子）、较低的亲脂性（ΔlogPoct−0.006），C-D键短于C-H键。D的摩尔质量是H的2倍（图1a）。因此，与C-H键相比，C-D键的振动频率降低，基态能量降低，进而解离活化能增加（图1b）。由此可见，C-D键比C-H键更稳定（差异为1.2-1.5kcal mol−1），其裂解速度较慢。这种差异可以通过氘动力学同位素效应（DKIE）来量化，DKIE表示为速率常数的比率（kH/kD）：DKIE值越高，C-D键断裂速率较C-H值越慢。当C-H裂解速率与C-D裂解速率进行比较时，就会出现初级同位素效应，数值在1到5之间。在特殊情况下，DKIEs可能是<1或>5，其理论上限值为9。然而，考虑到DKIE积累，同位素取代从分子中的远端（即远端DKIE）影响裂解，DKIE可能会达到显著的值并减缓化学键裂解的速率，对酶催化的过程产生深远影响，因此可以从不同的角度利用氘代来改善药物特性（图2）。图1 氘代动力学的同位素（DKIE）效应图2 药物氘代对其药物活性的影响02氘代药物的获益超过一半的已上市药物是由细胞色素P450（CYP）家族中的酶代谢的。但氧化代谢可能存在代谢物相关的风险：形成不稳定、反应性、非选择性和有毒的中间体和/或代谢物；基因多态性导致患者间代谢产物种类或比例差异；以及同工酶的饱和、诱导或抑制，导致潜在的药物-药物相互作用。因此，基于DKIE的D替代H，是药物开发过程中减弱CYP介导的代谢及其改变固有缺点的策略（图1c）。重要的是，为了观察到显著的DKIE和D对氧化代谢速率的影响，催化循环必须包括C–D键断裂。此外，DKIE的大小取决于代谢途径、所涉及的酶和特定底物。一般来说，O-脱烷基化是对氘代最敏感的反应，其次是酰胺N-脱烷基化和烷基的氧化。相反，胺的N-脱烷基化是最不敏感的转化，芳基羟基化不受H被D取代的影响（图1d）。03氘代药物的PK优势药物研发者利用氘代改构引起的药物代谢速度改变,主要从以下方面优化药物：①氘代改构通常会降低清除率，增加药物半衰期，从而增加体循环暴露量；②对于具有显著首过效应的药物，氘代改构可降低其首过效应，从而增加口服生物利用度；③氘代改构可减少特定代谢产物的形成，从而改善代谢谱；④立体异构体手性中心的氘代改构可减少立体异构体间的相互转化，从而稳定单一立体异构体。降低清除率,增加体循环暴露量：CTP-656是原研药物Ivacaftor(商品名:Kalydeco®)的氘代形式，其目标适应证与Ivacaftor相同，即用于治疗囊性纤维化跨膜传导调节因子特定突变所致的囊性纤维化。体外实验结果显示：CTP-656的药理活性与Ivacaftor相似，但氘代改构明显减缓其代谢速度(主要为CYP3A4和CYP3A5催化的烷基氧化反应)。动物实验中，10.0 mg·kg-1剂量下,大鼠口服给予CTP-656后的Cmax、t1/2和AUC分别为Ivacaftor的1.03、1.26和1.09倍。犬口服给予CTP-656后的Cmax、t1/2和AUC分别为Ivacaftor的1.54、1.29和1.69倍。CTP-656的首次人体试验结果显示：与Ivacaftor 25 mg的历史数据相比，健康受试者口服给予CTP-656 25 mg后的AUC、Cmax、t1/2均具有增加趋势。降低首过效应,增加口服生物利用度：Atazanavir(商品名:Reyataz®)为口服人类免疫缺陷病毒(human immunodeficiency virus,HIV)蛋白酶抑制剂(protease inhibitor,PI)，常与利托那韦联合用于治疗HIV-1感染。Atazanavir的肝首过效应较强,经CYP3A4/CYP3A5广泛代谢,口服生物利用度较低(大鼠为15%；犬为36%)。利托那韦既是HIV-PI，也是CYP3A强抑制剂，可作为PK增强剂增加Atazanavir的口服生物利用度,从而获得更好的抗病毒效果。但利托那韦会造成高脂血症、高血糖症和胃肠道不耐受等不良反应。CTP-518是Atazanavir的氘代形式，其研究者希望通过氘代改构，开发出既保持Atazanavir抗病毒活性，又无需合用利托那韦或其他PK增强剂的HIV-PI。体外实验结果显示:CTP-518与Atazanavir具有相似的抗病毒活性,而在人肝微粒体中的半衰期增加51%。动物实验中,猴静脉给药后，CTP-518的半衰期比Atazanavir增加52%。减少特定代谢产物,改善代谢谱：帕罗西汀(商品名:Paxil®)为一种抗抑郁药,也是常见的CYP2D6抑制剂。其经CYP2D6代谢形成的卡宾类代谢产物会与CYP2D6形成不可逆复合物,进而抑制CYP2D6活性,并减缓其本身的代谢速度。CTP-347是帕罗西汀的氘代形式,体外实验显示二者的药理活性相似,但对CYP2D6的抑制程度不同。首次人体试验结果显示:健康受试者口服给予CTP-347 10 mg,qd,连续14 d的暴露量低于相应剂量的帕罗西汀(第1天AUC0-t:8.3 vs 17.8 ng·mL-1·h;第14天AUC0-t:18.0 vs 248.1 ng·mL-1·h),蓄积系数也较低(2.9 vs 13.9)。并且与相应剂量的帕罗西汀历史数据相比,CTP-347 20 mg,qd连续给药对CYP2D6模型底物(右美沙芬)代谢的影响较小。该结果提示：氘代改构减少卡宾类代谢产物，减弱药物对CYP2D6的抑制作用，从而减少其与CYP2D6底物的相互作用。04氘代药物研究进展在过去的20年里，有几家公司致力于氘代药物的开发，由此也吸引了大量资本的关注及注入，截止到目前为止，总交易已超过70亿美元。随着资本的注入和技术的完善，FDA于2017年批准了Deutetrabenazine的上市，2021年，中国和乌兹别克斯坦分别批准了Donafenib和VV116的上市。Deutetrabenazine的上市，为致力于氘代药物的开发看到了希望，迄今为止，至少有15个候选药物正在进行临床试验（表1），其中6个处于III期。表1 处于临床试验阶段的氘代药物研究进展05氘代药物的机遇与挑战虽然D在药物发现中的使用有诸多优势，但它也有一些缺点。图3中的SWOT分析总结了氘化方法的主要优缺点，以及机会和挑战。图3 氘化方法的SWOT分析能够在不显著改变其空间位阻或电子性质的情况下增加分子对键裂解的抵抗力，这是氘代药物的最大优势。D原子对药物吸收、分布、代谢、排泄和毒性（ADMET）整体特性的影响超出了代谢。虽然H和D之间的亲脂性的差异是可以忽略的，当多个D原子存在时，可能导致血浆蛋白结合率的改变。氛代策略中，氘代甲基CD3的引入是最为普遍、最为便捷的策略。该策略氘源便宜，成本较低，能满足放大生产需求；反应收率高，CD3相对稳定，氘不易丢失；而且根据需要可在合成工艺的初始和后期步骤中引入CD3，使得工艺更加灵活。尽管CD3甲基限定了这类氘代药物的结构，但随着过渡金属催化C-C偶联反应的快速发展，CD3I可以直接与卤代芳烃进行偶联，从而在芳环上引入CD3，这将极大推动CD3药物的发展。对于金属催化1H-D交换策略，位置选择性和氘代率是一个难题，这限制了此策略的应用。弱酸弱碱催化相对温和，对于活泼质子的氘代是不错的策略。但对于需要强酸强碱条件，底物的耐受性也是一个挑战。所以，对于结构多样的药物分子来说，以D2O为氘源，发展均相的选择性1H-D交换金属催化剂，将是一个重要的研究方向。参考文献：Di Martino RMC, Maxwell BD, Pirali T. Deuterium in drug discovery: progress, opportunities and challenges. Nat Rev Drug Discov. 2023 Jul;22(7):562-584. doi: 10.1038/s41573-023-00703-8. Epub 2023 Jun 5. PMID: 37277503; PMCID: PMC10241557.Sharma D, Chatterjee R, Dhayalan V, Dhanusuraman R, Dandela R. Recent Advances in the Practical Synthesis of C1 Deuterated Aromatic Aldehydes Enabled by Catalysis and Beyond. Chem Asian J. 2022 Sep 14;17(18):e202200485. doi: 10.1002/asia.202200485. Epub 2022 Aug 10. PMID: 35844079.Pirali T, Serafini M, Cargnin S, Genazzani AA. Applications of Deuterium in Medicinal Chemistry. J Med Chem. 2019 Jun 13;62(11):5276-5297. doi: 10.1021/acs.jmedchem.8b01808. Epub 2019 Jan 25. PMID: 30640460.胡涛,张海波,梁慧兴等.临床试验的氘代药物及其氘代合成策略[J].精细化工中间体,2022,52(01):1-6+23.DOI:10.19342/j.cnki.issn.1009-9212.2022.01.001.