TH-1904

MONTREAL, Oct. 22, 2021 (GLOBE NEWSWIRE) -- Theratechnologies Inc.. (Theratechnologies, or Company) (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, is pleased to announce the publication of a peer-reviewed article demonstrating that the Company’s novel investigational peptide-drug conjugates (PDCs) TH1902 and TH1904, derived from its SORT1+ Technology™, are effective in inhibiting vasculogenic mimicry (VM) in in vitro ovarian and triple negative breast cancer (TNBC) models. The article was published in the science journal Frontiers in Oncology and is titled “New Peptide-Drug Conjugates for Precise Targeting of SORT1-Mediated Vasculogenic Mimicry in the Tumor Microenvironment of TNBC-Derived MDA-MB-231 Breast and Ovarian ES-2 Clear Cell Carcinoma Cells.” “The results published in Frontiers in Oncology showcase for the first time that the sortilin receptor plays a role in the formation of VM, which is associated with cancer progression and resistance. By targeting SORT1, TH1902 and TH1904 have the potential to inhibit VM and cancer cell growth,” said Dr. Christian Marsolais, Senior Vice President and Chief Medical Officer at Theratechnologies. “This recognition by our scientific peers highlights the great potential of our PDCs as a unique and effective vehicle for the potential treatment of many types of cancers in which SORT1 receptors are overexpressed and provides additional evidence that SORT1 plays a major role in the generation of VM, particularly in TNBC and ovarian cancer.” The article is the first to report that SORT1 plays a key role in VM formation and highlights the novel results from preclinical models evaluating the efficient inhibitory properties of TH1902 and TH1904 against VM in in vitro ovarian and TNBC cell models. These results further support the expectation that TH1902 and TH1904 may alter the VM process by bringing anticancer drugs, like docetaxel and doxorubicin, into SORT1-positive cancer cells. The article can be accessed online here. About Vasculogenic Mimicry The formation of microvascular channels by deregulated cancer cells leads to aggressive, metastatic and resistant cancer cells and is known as vasculogenic mimicry. VM is believed to be associated with tumor growth, resistance and poor prognosis in many types of aggressive cancers including ovarian and TNBC. About SORT1+ Technology™ Theratechnologies is currently developing a platform of new proprietary peptides for cancer drug development targeting SORT1 receptors called SORT1+ TechnologyTM. SORT1 is a receptor that plays a significant role in protein internalization, sorting and trafficking. It is highly expressed in cancer cells compared to healthy tissue making it an attractive target for cancer drug development. Expression has been demonstrated in, but not limited to, ovarian, triple-negative breast, endometrial, skin, lung, colorectal and pancreatic cancers. Expression of SORT1 is associated with aggressive disease, poor prognosis and decreased survival. It is estimated that the SORT1 receptor is expressed in 40% to 90% of cases of endometrial, ovarian, colorectal, triple-negative breast and pancreatic cancers. The Company’s innovative peptide-drug conjugates (PDCs) generated through its SORT1+ TechnologyTM demonstrate distinct pharmacodynamic and pharmacokinetic properties that differentiate them from traditional chemotherapy. In contrast to traditional chemotherapy, Theratechnologies’ proprietary PDCs are designed to enable selective delivery of certain anticancer drugs within the tumor microenvironment, and more importantly, directly inside SORT1 cancer cells. Commercially available anticancer drugs, like docetaxel, doxorubicin or tyrosine kinase inhibitors are conjugated to Theratechnologies’ PDC to specifically target SORT1 receptors. This could potentially improve the efficacy and safety of those agents. In preclinical data, the Company’s SORT1+ TechnologyTM has shown to improve anti-tumor activity and reduce neutropenia and systemic toxicity compared to traditional chemotherapy. Additionally, in preclinical models, SORT1+ TechnologyTM has shown to bypass the multidrug resistance protein 1 (MDR1; also known as P-glycoprotein) and inhibit the formation of vasculogenic mimicry - two key resistance mechanisms of chemotherapy treatment. About TH1902 TH1902 combines Theratechnologies’ proprietary peptide to the cytotoxic drug docetaxel. TH1902 is currently Theratechnologies’ lead investigational PDC candidate for the treatment of cancer derived from its SORT1+ Technology™. The FDA granted fast track designation to TH1902 as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. TH1902 is currently being evaluated in a Phase 1 clinical trial for the treatment of cancers where the sortilin receptor is expressed. The Company is also evaluating TH1904 in preclinical research, a second PDC derived from its SORT1+ TechnologyTM TH1904 is conjugated to the cytotoxic drug doxorubicin. The Canadian Cancer Society and the Government of Quebec, through the Consortium Québécois sur la découverte du médicament (CQDM), contributes a total of 1.4 million About Theratechnologies Theratechnologies (TSX: TH) (NASDAQ: THTX) is a biopharmaceutical company focused on the development and commercialization of innovative therapies addressing unmet medical needs. Further information about Theratechnologies is available on the Company's website at , on SEDAR at and on EDGAR at . Forward-Looking Information This press release contains forward-looking statements and forward-looking information, or, collectively, Forward-Looking Statements, within the meaning of applicable securities laws, that are based on our management’s beliefs and assumptions and on information currently available to our management. You can identify Forward-Looking Statements by terms such as "may", "will", "should", "could", “would”, "outlook", "believe", "plan", "envisage", "anticipate", "expect" and "estimate", or the negatives of these terms, or variations of them. The Forward-Looking Statements contained in this press release include, but are not limited to, statements regarding the use of TH1902 and TH1904 for the potential treatment of sortilin-positive TNBC and other sortilin-expressed cancer types, and the conduct of our clinical trial with TH1902. Although the Forward-Looking Statements contained in this press release are based upon what the Company believes are reasonable assumptions in light of the information currently available, investors are cautioned against placing undue reliance on these statements since actual results may vary from the Forward-Looking Statements. Certain assumptions made in preparing the Forward-Looking Statements include that: the current COVID-19 pandemic will have limited adverse effect on the Company’s operations and its business plan; the Company will succeed in pursuing the conduct of its Phase 1 clinical trial using TH1902; preclinical in vitro results will be replicated into humans; research and development activities using peptides derived from its SORT1+ TechnologyTM will yield positive results allowing for the development of new drugs for the treatment of cancer; and the Company’s business plan will not be substantially modified. Forward-Looking Statements assumptions are subject to a number of risks and uncertainties, many of which are beyond Theratechnologies’ control that could cause actual results to differ materially from those that are disclosed in or implied by such Forward-Looking Statements. These risks and uncertainties include, but are not limited to, those related to or arising from: the adverse impact of the ongoing COVID-19 pandemic on (a) the Company’s sales efforts and sales initiatives, (b) the capacity of the Company’s suppliers to meet their obligations vis-à-vis the Company, (c) the Company’s research and development activities, (d) the health of the Company’s employees and its capacity to rely on its resources, as well as (e) global trade; the Company’s ability to successfully conduct its Phase 1 clinical trial using TH1902 in various types of cancer; the Company’s capacity to acquire or in-license new products and/or compounds; and the Company’s estimates regarding its capital requirements. We refer current and potential investors to the “Risk Factors” section of our Annual Information Form dated February 24, 2021 available on SEDAR at and on EDGAR at as an exhibit to our report on Form 40-F dated February 25, 2021 under Theratechnologies’ public filings for additional risks related to the Company. The reader is cautioned to consider these and other risks and uncertainties carefully and not to put undue reliance on Forward-Looking Statements. Forward-Looking Statements reflect current expectations regarding future events and speak only as of the date of this press release and represent our expectations as of that date. We undertake no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise, except as may be required by applicable law. For media and investor inquiries: Leah Gibson Senior Director, Investor Relations ir@theratech.com 617-356-1009

近年来，多肽作为后基因时代的热点，已被广泛应用于药物开发中。多肽可对靶点表现出精湛的亲和力与特异性，同时可转化为高效药物，使副作用显著降低。科学家们积极开发多肽偶联药物（PDC），弥补传统小分子化学药的缺陷，实现药物的精准投递，以较低的剂量、更高的效率治疗肿瘤。         截止目前，全球范围内已有两款PDC产品获批，另有多款PDC产品已进入临床阶段。这一领域已吸引很多生物医药公司的关注，其中既包括诺华（Novartis）、阿斯利康（AstraZeneca）、罗氏（Roche）等在内的大型医药公司，也有多家中国公司，他们都在进行PDC产品的开发。为何PDC能从众多药物形式中脱颖而出、备受业内青睐？          PDC简介 PDC（Peptide Drug Conjugate） ，是一种新型的偶联药物，其结构主要包含3个元素--细胞毒素，Linker以及靶向多肽，通过一个可分解的Linker将特定的多肽序列与细胞毒素共价结合。它将细胞毒素以提高局部浓度的形式靶向递送至患病组织，减轻非疾病组织中的毒性效应，从而减轻不良反应，达到增效减毒的科学目的。        PDC药物作用机制（来源：参考1）         PDC产品优势 PDC整合了多肽的优势，具有较小的分子量，可生物降解同时不会引起免疫原性反应。PDC可通过修饰肽链的氨基酸序列改变共轭疏水性和电离性质，解决水溶性差、代谢不及时等问题，同时促进细胞通透性，避开了小分子药物由于理化性质欠佳在临床开发中的磨损率较高这一难关。此外，低分子量的PDC更容易通过HPLC技术得到纯化，这在药代动力学中亦至关重要。PDC很大程度上提供了一个更灵活的药代动力学优化平台。与抗体偶联药物（Antibody Drug Conjugate，ADC）相比，其分子量更小，不易引起自身免疫反应；与抗体生产的复杂工艺过程相比，PDC更易合成与纯化，有效降低大规模生产的成本。         PDC产品三要素 PDC是一类靶向治疗药物，其结构与抗体偶联药物(ADC)类似，但在设计上有所不同。PDC由归属肽（Homing Peptide，即细胞靶向多肽）、连接子、有效载荷三部分组成，这三个部分协同将细胞毒性药物通过特定受体递送至肿瘤细胞。        PDC结构示意图（来源：参考2）         (1)细胞毒素         细胞毒素被当作"有毒弹头"应用在PDC中，未加修饰的原始细胞毒素如不与靶向肽结合，其将癌细胞与正常细胞区分开的能力较差，毒性不受控制的缺点暴露无遗。细胞毒素通过合适的载体有效地交付给肿瘤组织去对抗其高疏水性，从而增强细胞毒素的药代动力学和治疗窗口。         (2)Linker         Linker的选择是PDC设计中的关键因素之一。根据其长度、稳定性、释放机理、官能团、亲/疏水性等特征，PDC中使用的Linker存在多种不同类型。         (3)多肽         在PDC药物中，多肽最主要的功能是实现靶向定位。多肽与抗体的组成和连接方式均相同，都是由氨基酸通过肽键连接而成，不同的是，多肽相较于抗体，分子量更低，通常不具备蛋白质三级结构。多肽普遍存在于生物体内，其广泛参与和调节机体内各系统、器官、组织和细胞的功能活动，在生命活动中发挥重要作用。因此也成为PDC药物"另辟新径"的基础。         重要的是，多肽相较于抗体更大的优势是生产成本和技术积累。特别是多肽作为治疗性药物也有长期的实践应用，因此，国内企业在考虑创新转型时，更多的也具备多肽的生产技术和设备，特别是固相合成、酶催化合成等多肽合成手段的应用。         PDC已获批产品 诺华--177Lu-dotatate（商品名Lutathera）         2018年初，FDA批准诺华公司生产的创新性抗癌药 Lutathera（镥氧奥曲肽）上市，用于治疗成人生长抑素受体阳性的胃肠胰腺神经内分泌肿瘤。         Lutathera是一种Lu-177标记的生长抑素类似物，属于肽受体放射性核素疗法（PRRT）。该药物的机理是：通过与一种称为生长激素抑制素受体的细胞结合而起作用，该生长抑素受体可能存在于某些肿瘤上。在与受体结合之后，药物进入细胞，释放辐射来损伤肿瘤细胞。         除了用作治疗的药物之外，携带放射性核素的PDC还被成功开发为一类疾病诊断工具。         Oncopeptides公司--Pepaxto（melphalan flufenamide，也被称为melflufen）         2月26日，生物医药公司Oncopeptides宣布，FDA加速批准了其PDC药物Pepaxto（melphalan flufenamide，也被称为melflufen）上市，用于联合地塞米松治疗接受过至少四种治疗前期方法，且至少对一种蛋白酶体抑制剂、一种免疫调节剂和一种靶向CD38的单克隆抗体耐药的复发/难治性多发性骨髓瘤（R/R MM）成人患者。公开资料显示，Pepaxto采用创新技术将多肽与细胞毒性药物连接，产生亲脂性化合物并分布在细胞中，通过靶向MM细胞中过度表达的氨肽酶，进而将细胞毒性药物带入MM细胞中释放。         近期，另一家名为Theratechnologies的生物医药公司也公布了其研发管线中两款PDC的研究进展。其中，TH1902是以多西他赛为有效载荷的PDC，拟开发用以治疗三阴性乳腺癌和卵巢癌。另一款TH1904则以多柔比星为有效载荷，拟开发治疗卵巢癌。这两款PDC均是以神经降压素受体3（SORT1，也称为NTSR3）为靶点。         SORT1，也称神经降压素受体3，是一种膜结合受体，属于V P S10P受体家族。SORT1在向细胞内运输和分选各种配体（包括神经降压素、颗粒蛋白前体和载脂蛋白 E）方面发挥着不同的作用。另一方面，在许多类型的人类癌症中也观察到 SORT1 的上调，如乳腺癌、卵巢癌、胰腺癌和黑色素瘤以及垂体腺瘤。         在药物的结构形式上，TH1902应该算是常规的偶联药物形式。目前，TH1902已经进入临床Ⅰ期研究，计划Q4发布早期的安全性和有效性数据。2021年初，FDA也曾授予TH1902单药治疗标准疗法难治的分拣蛋白（sortilin）阳性复发性晚期实体瘤的快速通道认证。         另一款TH1904则以多柔比星为有效载荷，拟开发治疗卵巢癌。根据Theratechnologies公司官方资料，与传统化疗相比，TH1902和TH1904可将抗癌活性成分选择性递送至癌细胞中的SORT1上，抗癌活性成分迅速被癌细胞内化从而释放。临床前研究表明：与单独使用多西他赛相比，结合了靶向SORT1受体的多肽、连接子和多西他赛的TH1902具有更好的抗转移活性，且耐受性更佳。         与小分子和生物制品相比，尽管PDC在临床试验中取得的进展仍较少，但其多功能性以及许多优势意味着PDC是一个发展前景广阔的研究领域。而中国正在经历生物类似药、PD-1/L1、ADC药物扎堆的时代，PDC药物或许将是中国偶联药物开发企业另辟蹊径所在。         参考来源：        1. Paul Hoppenz,Sylvia Els-Heindl and Annette G.Beck-Sickinger. Peptide-Drug Conjugates and Their Targets in Advanced Cancer Therapies. Fronters in Chemistry. 2020, 8, 571.         2. Bethany M Cooper，et al（2021）. Peptides as a platform for targeted therapeutics for cancer: peptide-drug conjugates (PDCs). Chem Soc Rev ,DOI：10.1039/D0CS00556H.         3.Bethany M Cooper，et al. Peptides as a platform for targeted therapeutics for cancer: peptide-drug conjugates (PDCs). Chem Soc Rev, 2021, 50, 1480-1494.