IL-33

9月6日，葛兰素史克（GSK）宣布，其IL-5抗体Nucala（mepolizumab，美泊利珠单抗）治疗COPD的3期MATINEE研究取得了积极结果。相比于安慰剂组，Nucala治疗组中重度恶化年化率得到统计学意义的显著下降，但具体数据尚未公布。 两个月前，两个新机制COPD药物：ensifentrine和dupilumab相继在美国和欧洲获批上市，刷新了这一严重呼吸系统疾病的治疗模式，mepolizumab有望加入这新一轮的竞争。 COPD：人类第三大死因 慢性阻塞性肺疾病（COPD,chronic obstructive pulmonary disease）简称慢阻肺，一种常见的、可以预防和治疗的异质性疾病。 根据世界卫生组织统计，COPD已经成为人类的第三大死因，约有11%的人死于COPD。预计未来40年COPD的患病率将不断增加，到2060年每年可能会有超过540万人死于COPD及其相关疾病。2018年王辰院士在《The Lancet》上发表的研究显示，我国就有近1亿COPD患者，40岁以上成人COPD患病率达13.7%。 根据贝哲斯咨询发布的慢性阻塞性肺病(COPD)市场研究报告显示，2023年全球慢性阻塞性肺病(COPD)市场规模为214.4亿美元，预计在2023-2028年预测期内该市场将以4.3%的复合年增长率增长。 COPD药物开启新一轮竞争 目前，COPD的治疗和预防药物主要有吸入性糖皮质激素、支气管扩张剂、磷酸二酯酶-4抑制剂、抗生素、疫苗、黏液溶解剂及抗氧化剂。这些药物虽然对于COPD患者的症状有显著改善，但COPD急性加重的预防仍是目前的治疗难点。 Mepolizumab是一种白细胞介素5（IL-5）受体抑制剂，能特异性结合IL-5，并阻止其激活IL-5受体，于2015年11月首次获得美国FDA批准用于严重哮喘，商品名为Nucala。此后，该药又获批了慢性鼻窦炎和高嗜酸性粒细胞综合征等其他适应症。 MATINEE研究是一项为期104周的多中心、随机、双盲、安慰剂对照临床试验，评估Nucala对比安慰剂作为疾病频繁恶化且血嗜酸性粒细胞水平升高的中度至重度COPD患者在维持治疗之外的附加治疗方案的有效性和安全性。研究的主要终点为中度至重度COPD的年恶化率。 结果显示，Nucala加上吸入维持治疗在长达104周的时间里，显著降低了COPD患者中度或重度急性加重的年发生率。 今年第二季度，Nucala销售额达到4.82亿英镑（6.347亿美元），同比增长17%。Nucala如果能顺利获批扩展适应症用于COPD，未来销售额有望进一步增长。 但它不会是唯一的新选择。 今年6月，FDA批准了Verona Pharma的Ohtuvayre(ensifentrine)上市，这是20多年来FDA批准的首个具有新机制的COPD维持疗法。该药是一种小分子选择性磷酸二酯酶双抑制剂（PDE3/4），具有支气管舒张和抗炎的双重作用。 7月，欧洲药品管理局（EMA）批准了赛诺菲和再生元联合开发的Dupixent(度普利尤单抗)作为以血嗜酸性粒细胞水平升高为特征的不受控制的慢性阻塞性肺病（COPD）患者的附加维持治疗，成为COPD治疗领域的首个获批生物制剂。该药本月也有望获得美国FDA批准，PDUFA日期为9月27日。 此外，还有更多药企正在开发COPD新药，包括再生元的IL33单抗itepekimab、阿斯利康/安进的TSLP单抗Tezspire(tezepelumab)等。 表1 COPD领域在研新药（部分） 数据来源：药智数据 另外，国内也有众多药企加入COPD新药竞争，包括正大天晴的PDE3/4抑制剂TQC-3721、康诺亚的IL-4Rα单抗司普奇拜单抗（CM310）等。 结语 COPD领域在过去很多年都无新机制药物上市，但今年这一格局发生了变化。 Verona公司的ensifentrine和再生元/赛诺菲的度普利尤单抗相继获批了COPD适应症，GSK的mepolizumab也获得三期临床积极结果。另外还有多个靶向炎症通路的生物制剂正在开展三期临床研究。预计很快，COPD领域将掀起新一轮的竞争。 声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。 责任编辑 | 小月石 转载开白 | 马老师 18996384680（同微信） 商务合作 | 王存星 19922864877（同微信）  阅读原文，是受欢迎的文章哦

Tozorakimab performed better in patients who had experienced moderate or severe exacerbations in the past year. AstraZeneca executives say they are “not worried” that the failure of tozorakimab in a phase 2 chronic obstructive pulmonary disease (COPD) trial will throw their plans for the anti-IL-33 monoclonal antibody off track.The U.K.-based Big Pharma unveiled data from the phase 2 FRONTIER-4 study at the European Respiratory Society 2024 Congress in Vienna, Austria on Sunday. The study saw 135 COPD patients with chronic bronchitis receive either 600 mg of tozorakimab or placebo every four weeks for 12 weeks.The trial missed the primary endpoint of demonstrating an improvement in pre-bronchodilator forced expiratory volume (FEV), the amount of air that a person can exhale during a forced breath, according to the abstract.AstraZeneca is already running phase 3 trials of tozorakimab in patients who had experienced two or more moderate exacerbations or one or more severe exacerbations in the previous 12 months. When zooming into this sub-group in today’s phase 2 data, the company had better news—a 59 mL improvement in FEV.Among this subgroup, tozorakimab was also shown to reduce the risk of so-called COPDCompEx—a catch-all term for moderate and severe exacerbations as well as the study dropout rate—by 36%, the pharma noted. AstraZeneca's Caterina Brindicci, M.D., Ph.D., global head of respiratory and immunology late-stage development, BioPharmaceuticals R&D, told Fierce that today’s phase 2 fail would “not at all” impact the pharma’s late-stage strategy for tozorakimab.“In the phase 3 program we are targeting exactly the population where we saw a stronger signal in phase 2,” Brindicci said in an interview.Unlike other anti-IL-33 antibodies, tozorakimab has a dual mechanism of action that not only inhibits interleukin-33 signaling via the RAGE/EGFR pathway but also affects a separate ST2 receptor pathway involved in inflammation, Brindicci explained.“This dual pathway that we can target really gives us confidence that we will very likely have efficacy demonstrated in phase 3,” she added. “So we are not worried currently.”AstraZeneca is running a trio of phase 3 trials for tozorakimab in patients with a history of COPD exacerbations, with data set to read out “after 2025,” Brindicci said. There is also a late-stage trial ongoing in patients hospitalized for viral lung infection who require supplemental oxygen. Today’s readout isn’t the first time that tozorakimab has struggled in the clinic. Back in February, AstraZeneca dropped plans to develop the drug in diabetic kidney disease after it failed a phase 2 trial in that indication. A year earlier, the pharma stopped work on the molecule in atopic dermatitis.The company’s Big Pharma peers have also had some bad luck with IL-33. GSK dropped its candidate in 2019, and the following year Roche axed a candidate aimed at the IL-33 pathway after seeing asthma data.However, Sanofi and Regeneron overcame their own phase 2 setback and are now just weeks away from finding out if Dupixent will become the first biologic approved by the FDA for chronic COPD.

20 abstracts, including 4 oral presentations, offer new treatment insights for chronic obstructive pulmonary disease (COPD), asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) Data from landmark Phase 3 trials for Dupixent in COPD reinforce exacerbation reduction and improvement in lung function compared to placebo, and provide new assessments on health-related quality of life across patient subgroups Additional presentations spotlight a novel asthma imaging study showing the early impact of Dupixent on clinical remission, airway remodeling and mucus plugging starting at 4 weeks, as well as data from investigational therapy itepekimab in former smokers with COPD Aug. 26, 2024 -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced 20 abstracts across Dupixent® (dupilumab) and investigational therapy itepekimab will be presented at the European Respiratory Society (ERS) Congress 2024 being held from September 7 to 11 in Vienna, Austria. These clinical and real-world abstracts presented in collaboration with Sanofi include four oral presentations and demonstrate the potential of targeting key drivers of type 2 inflammation and other pathways to address respiratory diseases, such as COPD and asthma, and improve patient outcomes. “The breadth of our presentations at the ERS Congress showcase our commitment to advancing the management of a range of difficult-to-treat respiratory diseases,” said George D. Yancopoulos, M.D., Ph.D., Board co-Chair, President and Chief Scientific Officer at Regeneron, and a principal inventor of Dupixent. “Through our Dupixent clinical program, we have gained a deep understanding of the biology of airway diseases. We are now applying those insights to COPD, a complex and heterogenous disease, and are excited by the remarkable potential of our COPD research program investigating Dupixent, as well as our anti-IL-33 antibody itepekimab to support COPD patients regardless of smoking history.” Among the notable Dupixent presentations at ERS is a pooled analysis of the previously reported Phase 3 BOREAS and NOTUS trials in uncontrolled COPD with evidence of type 2 inflammation (i.e., raised blood eosinophils). In the trials, all patients were on background maximal standard-of-care inhaled therapy (with nearly all on triple therapy). BOREAS and NOTUS formed the basis of the recent European Commission approval and regulatory submissions around the world for Dupixent in certain patients with uncontrolled COPD. As shared in the abstract, the pooled analysis demonstrated that Dupixent patients (n=938) experienced a 31% reduction in the annualized rate of moderate or severe COPD exacerbations over 52 weeks compared to placebo (n=936; nominal p Additionally, new research will be shared from the Phase 4 VESTIGE trial, a novel imaging study evaluating the effects of Dupixent on airway remodeling in certain adults with asthma. Two poster presentations will show new data on the 4-week impact of Dupixent treatment on airway inflammation, volume, and flow, and mucus plugging, as well as outcomes for clinical remission after 4 and 24 weeks of treatment in adults with uncontrolled moderate-to-severe asthma. Dupixent, which was invented using Regeneron’s proprietary VelocImmune® technology, is a fully human monoclonal antibody that inhibits the signaling of the interleukin-4 (IL-4) and interleukin-13 (IL-13) pathways and is not an immunosuppressant. The Dupixent development program has shown significant clinical benefit and a decrease in type 2 inflammation in Phase 3 trials, establishing that IL-4 and IL-13 are key and central drivers of the type 2 inflammation that plays a major role in multiple related and often co-morbid diseases. Dupixent has received regulatory approvals in more than 60 countries in one or more indications including certain patients with atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis (EoE), prurigo nodularis, chronic spontaneous urticaria (CSU), and COPD in different age populations. More than 950,000 patients are being treated with Dupixent globally. Dupilumab is being jointly developed by Regeneron and Sanofi under a global collaboration agreement. To date, dupilumab has been studied across more than 60 clinical trials involving more than 10,000 patients with various chronic diseases driven in part by type 2 inflammation. In addition to the currently approved indications, Regeneron and Sanofi are studying dupilumab in a broad range of diseases driven by type 2 inflammation or other allergic processes in Phase 3 trials, including chronic pruritus of unknown origin and bullous pemphigoid. These potential uses of dupilumab are currently under clinical investigation, and the safety and efficacy in these conditions have not been fully evaluated by any regulatory authority. Itepekimab, which was invented using Regeneron’s proprietary VelocImmune technology, is a fully human monoclonal antibody that binds to and inhibits the signaling of interleukin-33 (IL-33), an initiator and amplifier of airway inflammation. Itepekimab is currently under clinical investigation in two COPD Phase 3 trials and its safety and efficacy have not been evaluated by any regulatory authority. Regeneron's VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's co-Founder, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved or authorized fully human monoclonal antibodies. This includes REGEN-COV® (casirivimab and imdevimab), Dupixent, Libtayo® (cemiplimab-rwlc), Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab-dgnb), Inmazeb® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz® (pozelimab-bbfg). Regeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous approved treatments and product candidates in development, most of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, neurological diseases, hematologic conditions, infectious diseases, and rare diseases. Regeneron pushes the boundaries of scientific discovery and accelerates drug development using our proprietary technologies, such as VelociSuite®, which produces optimized fully human antibodies and new classes of bispecific antibodies. We are shaping the next frontier of medicine with data-powered insights from the Regeneron Genetics Center® and pioneering genetic medicine platforms, enabling us to identify innovative targets and complementary approaches to potentially treat or cure diseases. The content above comes from the network. if any infringement, please contact us to modify.