Mepolizumab

A closely watched biologic drug for chronic obstructive pulmonary disease failed one of two large, late-stage studies, sending shares in its developers, Regeneron Pharmaceuticals and Sanofi, sliding downward Friday.While the drug, called itepekimab, met its goal in the other trial, the split findings cloud the prospects for Regeneron and Sanofi to seek approval on the basis of the current data. Instead, they may be forced to run a third Phase 3 study, analysts said, adding both time and cost to the therapys development.Regeneron shares were especially under pressure Friday morning, falling by more than 17%.The biotechnology company also faces lower-cost competitors to one of its top-sellers, the eye drug Eylea, and an end-of-decade patent expiration for another, the inflammatory disease treatment Dupixent. Sanofi shares slumped by about 6% in Nasdaq trading.COPD usually requires two positive Phase 3 results for regulatory approval, so we think one hit and one miss is unlikely to pave the way for commercialization, Baird analyst Brian Skorney wrote in a client note.Brian Abrahams, of RBC Capital Markets, expects at the very least an additional late-stage study will be necessary. If [Regeneron] and [Sanofi] are able to identify clear reasons for the divergent results, this may help the probability of success for a third [trial], but there would still be risk, he added in a separate note to investors.Regeneron and Sanofi, who are longtime development partners, designed the two trials of itepekimab similarly. Called AERIFY-1 and AERIFY-2, they each enrolled about 1,000 former smokers aged 40 years to 85 years who had moderate-to-severe COPD. Participants, who continued to take corticosteroids and other inhaled therapies, were randomized to receive different itepekimab doses or placebo.In the first study, treatment with itepekimab reduced the annualized rate of moderate or severe COPD attacks by 27% versus placebo on the every-two-week drug dose and 21% on the once-monthly dose at one year. Both reductions were statistically significant.But in the second, itepekimab every two weeks only reduced these so-called exacerbations by 2%, while the once-per-month dose lowered them by 12%. Neither result was statistically significant.While we are encouraged by the results of AERIFY-1, the results of both studies merit further exploration to have a full understanding of the data and the role that IL-33 plays in this complex disease, Houman Ashrafian, Sanofis head of R&D, said in a statement. An immune protein, IL-33 is itepekimabs target.Notably, the percentage reduction in attacks was greater at six months than it was at one year in both trials, raising questions about the durability of benefit.We don't have a particular hypothesis for why IL-33 inhibition would have an early positive effect followed by an acceleration in exacerbations but for a chronic treatment, we think it is something that would need to be clearly elucidated in longer studies, Skorney wrote.The companies said they are reviewing the data and plan to discuss it with health regulators. They noted that there were fewer COPD attacks overall in the studies than they had expected, decreasing the statistical power necessary for researchers to draw conclusions about inter-group differences. One possible reason, they hypothesized, was that enrollment mostly took place during the pandemic, potentially contributing to lower attack rates.Overall side effect rates were similar between the itepekimab and control groups, as were the rates of serious infections at about 7% to 10% across all arms in the two studies. Between 1% and 3% of adverse events led to death in the itepekimab arms, compared to 2% in the control cohorts.While itepekimabs future is now murkier, Regeneron and Sanofi do have a marketed COPD therapy in Dupixent, which won U.S. approval for that use last September. They were joined recently by GSK, which earlier this month secured regulatory clearance for its biologic COPD therapy Nucala.AstraZeneca, Roche and GSK are also developing IL-33 drugs for COPD, according to Jefferies analyst Andrew Tsai, although GSKs project is only in Phase 1 trials. '

//  •在临床试验和上市申请都晚于GSK的情况下，康诺亚实现反超率先获批上市；•康诺亚选择从度普利尤单抗尚未覆盖的鼻科适应症突破，实现差异化竞争；•康诺亚自建产能以控制成本，提升产品可负担性；•康诺亚全球首个靶向IL-4Rα生物制剂治疗季节性过敏性鼻炎的研究成果在顶刊发表；•康诺亚在积极布局下一代重磅自免双抗。“依靠司普奇拜单抗本身更具潜力的空间结构和更贴近中国人群临床需求的试验设计，我们在慢性鼻窦炎伴鼻息肉的临床试验里拿到了在监管层面更具说服力和竞争力的数据。”康诺亚创始人王常玉博士告诉研发客。由此，司普奇拜单抗在临床试验和上市申请都晚于美泊利珠单抗的情况下，获得了国家药监局的优先审评审批而率先获得批准。过去半年间，康诺亚拿到了自研新药司普奇拜单抗针对慢性鼻窦炎伴鼻息肉和季节性过敏性鼻炎的新药上市批件。在国内，司普奇拜单抗是首款针对这两个鼻科适应症获批上市的生物制剂，此前已获批用于治疗成人中重度特应性皮炎。“在季节性过敏性鼻炎适应症上，司普奇拜单抗更是成为了目前全球唯一的IL-4Rα抗体药物。”王常玉说。对比看来，赛诺菲的度普利尤单抗虽然也拥有成人中重度特应性皮炎适应症，但上述两项鼻科适应症尚未在国内获批。GSK的靶向IL-5美泊利珠单抗今年1月获批慢性鼻窦炎伴鼻息肉适应症，时间晚于司普奇拜单抗。阿斯利康/安进的靶向TSLP特泽利尤单抗，今年2月才在国内递交了治疗慢性鼻窦炎伴鼻息肉的上市申请。在MNC之外，正大天晴、恒瑞医药等多家本土企业的国产IL-4Rα单抗已推进临床Ⅲ期，不久的将来可能会加入竞赛。从疗效到价格全盘考虑度普利尤单抗在自免领域有先发优势，康诺亚选择从度普利尤单抗尚未覆盖的鼻科适应症突破，三个适应症协同配合，扩大了临床应用。慢性鼻窦炎伴鼻息肉、季节性过敏性鼻炎等疾病基本属于2型炎症。“在2型炎症即Th2通路中，IL-4Rα既影响Th2细胞分化，又控制IL-4及IL-13信号传导，占据着核心位置。而司普奇拜单抗可双重阻断IL-4和IL-13这两种引发2型炎症的关键细胞因子。”王常玉表示。“面对行业竞争，疗效始终是最重要的竞争筹码”，王常玉坦言，在临床获益方面康诺亚不惧进口产品的竞争。司普奇拜单抗独特的空间结构为其带来具有优势的临床潜力。司普奇拜单抗通过空间表位结合IL-4Rα，亲和力更高，生物活性更强。此外，此空间表位与细胞因子IL-4/IL-13同IL-4Rα相互结合位点邻近甚至重合，阻遏效果更好。据iScience发布的一篇文章，体外试验中司普奇拜单抗在阻断IL-4Rα介导的信号传导方面，与度普利尤单抗相当或更具优势。在慢性鼻窦炎伴鼻息肉治疗上，从非头对头的临床数据来看，司普奇拜单抗2周的治疗效果已超过美泊利珠单抗52周的表现。王常玉告诉研发客，已有真实世界的案例显示，有慢性鼻窦炎伴鼻息肉患者使用进口生物制剂3个月没有起效，转用司普奇拜单抗1个月后便看到了疗效。除了鼻科适应症，非头对头的中国人群数据对比还显示，司普奇拜单抗16周针对成人中重度特应性皮炎患者的疗效数据较度普利尤单抗同样具有竞争潜力。在去年欧洲EAACI年会上，康诺亚首次发布了司普奇拜单抗用于治疗成人中重度特应性皮炎的Ⅲ期临床研究52周疗效及安全性数据，52周EASI-75和EASI-90分别达到了92.5%和77.1%。拓展阅读52周大规模数据发布，这款IL-4Rα单抗能否站上C位？除了疗效和安全性，康诺亚也很早就考虑如何在生产上降本增效，以提升药物的可负担性。“国内生物药定价时生产成本占了很大的比重，若依靠CDMO，很难将成本真正降下来。所以康诺亚在2016年成立之初，便决定自建可覆盖大适应症需求的产能。”王常玉表示。全球首个相关研究成果登上顶刊过敏性鼻炎在我国的患病率持续攀升，即便经过常规治疗（联用鼻用激素与抗组胺药），仍有部分患者症状未能得到有效控制。慢性鼻窦炎伴鼻息肉，约50%的患者对传统治疗应答不足，嗜酸粒细胞型患者复发率更高达99%，传统药物及手术治疗难以从根源上抑制炎症复发。上述大量未被满足的治疗需求，既严重影响患者生活质量，又带来沉重的社会经济负担，已然成为我国不容忽视的公共卫生健康问题。今年4月，司普奇拜单抗治疗中重度季节性过敏性鼻炎的一项随机Ⅲ期试验结果在《自然·医学》（Nature Medicine）杂志发表，这是全球范围内首次报告基于IL-4Rα靶点的生物制剂治疗季节性过敏性鼻炎的研究成果。结果显示，治疗2天后司普奇拜单抗组患者鼻塞症状较安慰剂组显著改善；4天内实现鼻腔通气的患者达到52%；治疗2周和4周，分别有累计62%和84%的患者鼻部症状实现轻微或消失；治疗4周，累计94%的患者达到眼部症状轻微或消失。此外，司普奇拜单抗还可持续、显著改善眼部过敏症状，降低鼻腔分泌物中半胱氨酸蛋白酶抑制剂 SN（CST-1）、嗜酸性粒细胞活化趋化因子Eotaxin-3等2型炎症标志物水平。安全性方面，司普奇拜单抗治疗季节性过敏性鼻炎安全性良好，治疗期间不良事件（TEAE）发生率与安慰剂组相当，未发生治疗相关的严重不良事件。而针对于慢性鼻窦炎伴鼻息肉，司普奇拜单抗在Ⅲ期临床研究中也表现出了理想的疗效：首次用药2周，72%的患者鼻息肉显著缩小，24%的患者实现鼻腔通气，37%的失嗅患者恢复嗅觉；用药4周，有80%的患者鼻息肉显著缩小，42%的患者实现鼻腔通气，46%的失嗅患者恢复嗅觉，且长期使用的安全性良好。该研究的临床试验中心涵盖了我国大部分的行政区域，中国受试者样本量迄今最大（180例），填补了中国慢性鼻窦炎伴鼻息肉患者生物制剂随机对照试验的空白。近日，司普奇拜单抗被最新出版的《中国慢性鼻窦炎诊断和治疗指南(2024)》纳入，推荐为针对慢性鼻窦炎伴鼻息肉的生物制剂治疗选择。先站稳脚跟，再扩大成果在巩固鼻科领域先发优势的同时，康诺亚也在加速布局其他自免疾病、慢性病和癌症等适应症。来源|康诺亚官网去年，康诺亚启动了司普奇拜单抗针对结节性痒疹和青少年中重度特应性皮炎的Ⅲ期临床研究，目前研究进展顺利。双特异性抗体CM512针对慢性鼻窦炎伴鼻息肉、特应性皮炎、哮喘、慢性阻塞性肺疾病的临床研究正在快速推进，其中，慢性鼻窦炎伴鼻息肉Ⅱ期临床研究预计于今年启动。CM512被视作康诺亚下一代自免拳头产品，同时靶向TSLP和IL-13，可从早期抑制炎症级联反应的启动，有效减少Th2细胞分化和IL-13等细胞因子释放，同时直接抑制由IL-13驱动的病理症状，从而更有效地治疗2型炎症相关疾病。“基于目前的研究数据，CM512有潜力成为疗效更优、给药频率更低的治疗2型炎症相关疾病的药物。”王常玉表示。编辑 | 姚嘉yao.jia@PharmaDJ.com总第2449期访问研发客网站，深度报道和每日新闻抢鲜看www.PharmaDJ.com