NPSR1

关注并星标CPHI制药在线痛经，是许多女性的难言之隐。对于痛经严重的女性来说，每个月来例假就像是渡劫，严重影响正常的工作和生活。根据病因，痛经可分为原发性痛经和继发性痛经。继发性痛经主要是由盆腔器质性疾病引起，如子宫内膜异位症、子宫腺肌症、盆腔淤血综合征、先天性生殖道发育畸形（如阴道斜隔综合征）等。痛经是子宫内膜异位症的主要临床症状之一。       关于子宫内膜异位症       子宫内膜异位症（EMs，简称内异症）是由活性的内膜细胞种植在子宫内膜以外的位置而形成的一种常见的妇科疾病，主要表现为痛经、不孕症、慢性盆腔疼痛，严重影响女性的生殖健康和生活质量。       子宫内膜异位症在育龄女性中的发病率约为10%~15%，据世界子宫内膜异位症学会（WES）2014年统计，全球子宫内膜异位症发病人数超过2亿，亚洲的发病人数超过其他各大洲的总和。       目前，子宫内膜异位症的发病机制还不清楚，也无法治愈。当前，子宫内膜异位症已被纳入慢性疾病管理范畴，主流管理理念是尽量减少手术次数，最大化采取药物治疗。药物治疗的目的主要是缓解痛经，临床常用药物主要分为口服避孕药、非甾体类抗炎药、孕激素类药物、促性腺激素释放激素（GnRH）激动剂、促性腺激素释放激素（GnRH）拮抗剂、中医中药几类。       避孕药通过抑制排卵及负反馈抑制下丘脑-垂体-卵巢轴，形成体内低雌激素环境达到治疗效果。非甾体类抗炎药通过减少子宫内膜前列腺素合成来缓解痛经。       孕激素是治疗子宫内膜异位症最古老的药物，其通过抑制排卵及拮抗雌激素缓解痛经，临床上常用药物包括地诺孕素、地屈孕酮。       GnRH激动剂被认为是治疗子宫内膜异位症的"金标准"，其通过与垂体内的GnRH受体结合，持续占居GnRH受体并移入细胞内，使垂体卵泡刺激素（FSH）和黄体生成素（LH）分泌的节律消失，进而抑制卵泡发育及排卵，使血清雌激素达到绝经期水平，长期用药后异位内膜出现萎缩甚至"死亡"。       GnRH激动剂是人工合成的多肽药物，临床使用不便，而且其初期使用有点火效应，即初次应用GnRH激动剂时，其可短暂刺激腺垂体释放促性腺激素（FSH和LH），进而刺激卵巢激素的分泌。       GnRH拮抗剂近些年被开发用于治疗子宫内膜异位症，其也通过结合GnRH 受体发挥作用。早期开发的GnRH拮抗剂多为肽类，如西曲瑞克、加尼瑞克，应用于辅助生殖技术。针对子宫内膜异位症的GnRH拮抗剂是非肽类，其避免了GnRH激动剂的点火效应。       GnRH拮抗剂研究进展       目前，全球仅批准一款GnRH拮抗剂治疗子宫内膜异位症，即Orilissa（elagolix）。该药是由艾伯维与Neurocrine Bioscienc Chemicabookes共同研发的一款口服GnRH持抗剂，2018年7月被FDA批准用于治疗与子宫内膜异位症相关的中度至重度疼痛。       除了elagolix，全球还有多款在研GnRH拮抗剂被开发用于治疗子宫内膜异位症，如linzagolix、relugolix、CMS-D002、SHR7280、G201-Na、HS-10518。       其中linzagolix是Kissei自主研发的新型口服小分子GnRHR拮抗剂，2021年9月葆正医药获得其在中国的开发和商业化授权，2022年6月在欧盟被批准用于治疗子宫肌瘤相关的严重月经出血。目前，linzagolix针对子宫内膜异位症的临床试验处于3期阶段。       relugolix是武田研发的一款每日口服一次的GnRHR拮抗剂，2016年6月Myovant公司（Roivant和武田组建的公司）获得该药在日本和其他亚洲国家之外的全球独家授权，2019年1月在日本被批准用于改善子宫肌瘤引起的月经过多、下腹痛、腰痛和贫血。2020年12月，该药被FDA批准用于治疗成人前列腺癌。relugolix复方片（relugolix 40mg、雌二醇1.0mg、醋酸炔诺酮0.5mg）于2021年6月被FDA用于治疗绝经前女性子宫肌瘤相关月经大量出血。值得一提的是，relugolix复方片治疗子宫内膜异位症的3期临床试验已取得积极结果：与安慰剂相比，relugolix复方片显著减少了经期/非经期盆腔疼痛。       CMS-D002是康哲药业开发的一款小分子GnRHR拮抗剂，在临床前研究中表现出优异的有效性和安全性，近期在国内获批临床。       SHR7280是恒瑞医药研发的一种新型口服小分子GnRH受体拮抗剂。已公布的数据显示：该药在子宫内膜异位症相关疼痛治疗中显示出良好的安全性和药代动力学特性。药效学分析显示，SHR7280能够有效抑制雌二醇和黄体生成素浓度，并以剂量依赖的方式防止孕激素升高。       此外，催乳素受体靶向药（如HMI-115）、NK疗法也被开发用于治疗子宫内膜异位症。其中HMI-115是一种潜在"first-in-class"单克隆抗体，能够以非竞争性抑制的方式阻断催乳素下游的信号通路。2019年4月，和其瑞医药与拜耳签署一项全球独家许可协议，获得在全球开发和推广HMI-115用于治疗男性和女性脱发、子宫内膜异位症和其它与催乳素受体信号失调相关的慢性疾病的授权。2023年9月，和其瑞医药和鼎康生物达成战略合作，加速HMI-115的上市进程。       子宫内膜异位症领域的新发现       近年来子宫内膜异位症领域还有一些新发现。2021年《科学·转化医学》上发表的题为 Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis 的研究表明，NPSR1/NPS系统是一种经过基因分析验证的非激素靶标，与III/IV期子宫内膜异位症治疗的密切相关，可作为子宫内膜异位症非激素治疗的新靶点。       2023年《科学·转化医学》杂志上的发表的题为"Fusobacterium infection facilitates the development of endometriosis through the phenotypic transition of endometrial fibroblasts"的研究发现梭杆菌属感染会促进子宫内膜异位症的发展，抗生素治疗能有效减少实验动物病灶。       此外，2023年《The American Journal of Pathology》上发表的题为"Neurotrophins and Their Receptors, Novel Therapeutic Targets for Pelvic Pain in Endometriosis, Are Coordinately Regulated by IL-1β via the JNK Signaling Pathway"的研究表明，炎症、神经生长和痛觉的许多主要介质主要是通过JNK通路的一个选择性信号节点传递的，针对这一共同通路的药物有可能影响和改善子宫内膜异位症相关盆腔疼痛的多方面问题。【智药研习社近期课程预告】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~

Company's biologic drug candidate targets a key pathway involved in the progression and maintenance of depigmentation. TORONTO, ON / ACCESSWIRE / February 1, 2023 /Edesa Biotech, Inc. (Nasdaq:EDSA), a clinical-stage biopharmaceutical company focused on inflammatory and immune-related diseases, today announced that it has received approval from Health Canada for a Phase 2 clinical study of the company's EB06 monoclonal antibody candidate as a treatment for vitiligo. Vitiligo is a life-altering autoimmune disease that causes skin to lose its color in patches. While it can affect any area, vitiligo commonly occurs on the face, neck and hands, and is a lifelong condition. According to the World Health Organization, vitiligo affects approximately 1% of the world's population. Par Nijhawan, MD, Chief Executive Officer of Edesa, said that the regulatory clearance of the study represents a key part of the company's development and partnership plans for EB06. "This significant milestone in our vitiligo program provides us another novel Phase 2-ready asset and the opportunity to expand our discussions around partnering and advancing this late-stage biologic asset in our pipeline. Despite the high prevalence of vitiligo, there are few effective treatment options and no approved systemic therapeutics targeting the underlying disease." Edesa's drug targets autoreactive T cells that destroy the pigment-producing cells of the epidermis. Specifically, EB06 binds to chemokine ligand 10 (CXCL10) and inhibits the interaction of CXCL10 with its receptor(s). CXCL10 is highly expressed in vitiligo patients in both skin and serum, and CXCL10 is implicated in both the initiation of the disease and the maintenance of vitiligo lesions. Results from 65 subjects in three previous clinical studies demonstrated that EB06 produced the pharmacodynamic /biological activity required to address the dysfunctional immune response associated with vitiligo, and was generally safe and well tolerated. Preclinical studies have also demonstrated that neutralization of CXCL10 prevented and reversed depigmentation. "We believe there is significant scientific rationale to evaluate EB06's potential to prevent and reverse the highly visible symptoms of vitiligo, and we are excited about the potential of this program to change people's lives," said Dr. Nijhawan. As planned, the Phase 2 study protocol approved by Health Canada will evaluate the safety and efficacy of EB06 versus placebo in adults with moderate to severe non-segmental (generalized) vitiligo. Patients will receive intravenous infusions of either EB06 or placebo during the treatment period, followed by a follow-up period. Approximately 120 adult subjects will be included in the double-blind, placebo-controlled study at up to approximately 25 investigational centers in Canada. The primary endpoint will be improvement from baseline on the Face Vitiligo Area Scoring Index (F-VASI), a quantitative clinical tool that estimates the overall area of vitiligo patches and the degree of macular re-pigmentation within these patches over time. About Edesa Biotech Edesa Biotech, Inc. (Nasdaq:EDSA) is a clinical-stage biopharmaceutical company focused on developing innovative treatments for inflammatory and immune-related diseases with clear unmet medical needs. The company's two lead product candidates, EB05 and EB01, are in later stage clinical studies. Sign up for news alerts. Connect with us on Twitter and LinkedIn. Edesa Forward-Looking Statements This press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements may be identified by the use of words such as "anticipate," "believe," "plan," "estimate," "expect," "intend," "may," "will," "would," "could," "should," "might," "potential," or "continue" and variations or similar expressions, including statements related to: the company's belief that the CTA approval is a significant milestone and provides it with the opportunity to expand its discussions around partnering and advancing EB06; the potential efficacy of the drug in treating vitiligo and the relevance of EB06's mechanism of action against CXCL10; the company's belief that there is significant scientific rationale to evaluate EB06's potential to both prevent and reverse the highly visible symptoms of vitiligo; the drug's potential ability to change people's lives; and the company's timing and plans regarding its clinical development programs in general. Readers should not unduly rely on these forward-looking statements, which are not a guarantee of future performance. There can be no assurance that forward-looking statements will prove to be accurate, as all such forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause actual results or future events to differ materially from the forward-looking statements. Such risks include: the ability of Edesa to obtain regulatory approval for or successfully commercialize any of its product candidates, the risk that access to sufficient capital to fund Edesa's operations may not be available or may be available on terms that are not commercially favorable to Edesa, the risk that Edesa's product candidates may not be effective against the diseases tested in its clinical trials, the risk that Edesa fails to comply with the terms of license agreements with third parties and as a result loses the right to use key intellectual property in its business, Edesa's ability to protect its intellectual property, the timing and success of submission, acceptance and approval of regulatory filings, and the impacts of public health crises, such as Covid-19. Many of these factors that will determine actual results are beyond the company's ability to control or predict. For a discussion of further risks and uncertainties related to Edesa's business, please refer to Edesa's public company reports filed with the U.S. Securities and Exchange Commission and the British Columbia Securities Commission. All forward-looking statements are made as of the date hereof and are subject to change. Except as required by law, Edesa assumes no obligation to update such statements. CONTACT: Gary Koppenjan Edesa Biotech, Inc. (805) 488-2800 ext. 150 investors@edesabiotech.com SOURCE: Edesa Biotech View source version on accesswire.com:

A group of scientists from the Nuffield Department of Women's & Reproductive Health at Oxford University may have found a potential key to finally treating endometriosis, a disease that affects around 176 million women worldwide. In the study, Nuffield head and reproductive and genomic epidemiology professor Krina Zondervan and team conducted a genetic analysis of 32 families where at least three women had been diagnosed with endometriosis. They collected and sequenced DNA samples to study genetic linkage signals on chromosome 7p13-15 and found a significant overrepresentation of low-frequency coding variants in NPSR1. They also found the same receptor in their study of non-human primates (rhesus macaques, mouse models) with endometriosis. Although the authors said that further study is required to make conclusions, the findings give hope for a possible non-hormonal treatment approach for endometriosis. In an interview, Zondervan and co-author Dr. Thomas Tapmeier said that the decision to explore both human and non-human primate gene models is mainly because rhesus macaques menstruate the same way as women and can show similar endometriosis symptoms, like period pain and infertility. Endometriosis is a chronic inflammatory condition that causes pelvic pain and infertility in women, with limited treatment options and 50 percent heritability. At present, its treatment modalities are either surgical or hormonal. Typically, it takes eight years before women are diagnosed with the disease and, by this time, the symptoms are already apparent. NPSR1, the main point of the research, is responsible for encoding the protein Neuropeptide S receptor 1. Variations of this gene have previously been linked to other inflammatory diseases like inflammatory bowel disease and asthma and psychological problems like sleep disorders, panic attacks, and anxiety. In the latest study, the researchers found that the NPSR1 inhibitor SHA 68R blocked the NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro — all leading to a notable reduction of inflammatory cell infiltrate and abdominal pain in mouse models. Zondervan, Tapmeier, and their team said that further study is needed to understand the link between genetic variations in NPSR1 and tissue-specific functions of the receptor and the proteins where it binds.