Aurora B

近日，微芯生物公布了2023年三季报，前三季度公司实现营业收入3.49亿元，同比增长3.85%；扣非净利润为亏损1.96亿元。微芯生物作为中国原创新药领域的先行者，两款原创新药西达本胺和西格列他钠备受关注，今年前三季度销售收入分别为3.22亿元和1768万元，保持稳健增长。两款FIC新药2001年，在国内大多数药企还在做仿制药，少部分药企开始进行me-too、me-better式创新时，一家立志做“First in class”新药的公司在深圳成立。创始人鲁先平博士在成立微芯生物之前，在美国已经有两次创业经历，他参与创建的美国Maxia药物公司和Galderma Research生物技术公司先后被大型药企收购。成立之初，微芯生物分别获得了海达创投的500万元天使轮以及祥峰投资、泰达科投、北京科技风投的600万美元的A轮融资。2006年，微芯生物为缓解资金压力，以2800万美元将西达本胺的国外专利授权给美国生物技术公司沪亚生物，开创了国内创新小分子药向发达国家license out的先河。2015年，首款创新药西达本胺（Chidamide；商品名：爱谱沙）开启商业化销售，用于治疗外周T细胞淋巴瘤。2019 年西达本胺新增乳腺癌适应症。2023年，微芯生物提交了西达本胺第三个适应症的上市申请，用于治疗弥漫大B细胞淋巴瘤。2021年6月，西达本胺单药治疗成人T细胞白血病（ATL）适应症获日本医药品医疗器械综合机构（PMDA）正式批准，这是中国本土企业首个自主研发的原创新药在海外获批上市。今年3月，西达本胺在中国台湾获批乳癌适应症。西达本胺还在开展全球多中心一线黑色素瘤三期临床试验，以及联合不同抗肿瘤免疫治疗的多项临床试验研究。西达本胺是全球首个亚型选择性组蛋白去乙酰化酶(HDAC)口服抑制剂，属于机制新颖的、全球首个以实体肿瘤为适应症获批的表观遗传调控剂类药物。因为是对机制创新，所以西达本胺不仅可以应用于单一肿瘤症状，更可以通过联合表观遗传调控剂的肿瘤综合治疗，实现长期获益的路径。图1. 西达本胺抗肿瘤分子作用机制，图片来源：微芯生物官网2021年，微芯生物第二款创新药 西格列他钠（Chigltazar；商品名：双洛平）获批上市，是全球首个获批上市的PPAR全激动剂，用于治疗2型糖尿病。2023年6月，西格列他钠第二个适应症，联合二甲双胍上市申请获受理，申报适应症为治疗经二甲双胍单药控制不佳的型糖尿病。同时，西格列他钠治疗非酒精性脂肪肝炎（NASH）适应症正在开展2期临床试验。西格列他钠是一种过氧化物酶体增殖物激活受体（PPAR）全激动剂，能同时激活PPAR三个亚型受体(α、γ和δ)，并诱导下游与胰岛素敏感性、脂肪酸氧化、能量转化和脂质转运等功能相关的靶基因表达，抑制与胰岛素抵抗相关的PPARγ受体磷酸化。这是微芯生物首个针对代谢病治疗的药物品种。今年1月，西格列他钠通过医保谈判，被国家医保局纳入2022国家医保目录，为2型糖尿病患者提供了全新的治疗选择。从小分子到大分子，微芯生物管线储备丰富凭借自主创建的国际先进的“基于化学基因组学的集成式药物发现及早期评价平台”，微芯生物在肿瘤、代谢性疾病、自身免疫性疾病、中枢神经性疾病和抗病毒五个重大疾病领域已开发出多款潜在创新药。除了已上市的2个上市新药（西达本胺、西格列他钠），据微芯生物官网显示，公司还有4个进入临床开发阶段的产品，25+个在研新分子实体项目。图2. 微芯生物在研管线，图片来源：微芯生物官网西奥罗尼（Chiauranib）是微芯生物针对肿瘤的异质性及由此带来单一通路靶向药物在治疗中易产生耐药性的问题，自主设计、合成、筛选和开发的针对三通路的选择性激酶抑制剂。西奥罗尼具有对Aurora B/VEGFR /CSF1R靶点的高选择性抑制，能同时通过抑制肿瘤血管生成、抑制肿瘤细胞有丝分裂和调节肿瘤微环境三通路，发挥综合抗肿瘤作用，具有相对同类机制药物更优异的动物药效活性和良好的安全性。目前，西奥罗尼治疗小细胞肺癌、卵巢癌的临床3期正在全球开展中，肝癌、三阴性乳腺癌、非霍金淋巴瘤、其他神经内分泌肿瘤也已进入2期临床。CS12192是微芯生物在自身免疫疾病领域的首个品种，属于作用机制新颖高选择性JAK3激酶抑制剂，同时部分抑制JAK1和TBK1激酶。目前CS12192用于治疗类风湿性关节炎适应症正在进行1期临床试验，用于治疗移植物抗宿主病适应症正在美国已获批开展1期临床试验。CS32582是微芯生物在自身免疫疾病领域的另一个潜力单品。CS32582是一款酪氨酸激酶2（TYK2）高选择性小分子变构抑制剂，在临床前研究中显示出明确的有效性和良好的安全性，在动物体内口服生物利用度高。2023年10月31日，CS32582胶囊获得CDE批准开展治疗银屑病的临床试验申请。微芯生物在近几年大热的PD-1领域也迈出了重要的一步。CS23546是一款小分子PD-L1抑制剂。2023年6月25日，CS23546片获得CDE临床试验默示许可，拟开发用于治疗于晚期恶性肿瘤患者。CS23546 通过结合 PD-L1 并诱导其内吞从而解除 PD-1/PD-L1 信号通路介导的免疫抑制活性。CS23546 在临床前研究中显示出良好的口服吸收和肿瘤组织局部富集的代谢特征，单药针对不同肿瘤移植瘤模型均有显著抗肿瘤药效，联合化疗或公司自有品种如西达本胺和西奥罗尼则可产生显著的协同抗肿瘤活性。此次获批临床虽然离最后研发成功还有较长的路要走，但微芯生物在免疫治疗赛道上迈出了关键一步。除了擅长的原创新分子实体药物，微芯生物近两年加大了对大分子生物药特别是抗体药物的布局。2023年2月，微芯生物控股子公司微芯新域引进百奥赛图全资子公司祐和医药的双特异抗体新药 YH008大中华区权益，用于之后的开发探索与联用策略。微芯新域将向祐和医药支付 4000 万元人民币的首付款和后续不超过 3.6 亿元人民币的研发里程碑付款、后续不超过 1.96 亿元人民币的销售里程碑付款及根据年度净销售额在使用期限内支付一定比例的分级特许权使用费。YH008 目前已获得NMPA 和美国FDA IND 批准，拟用于治疗晚期肿瘤患者。此外，微芯生物针对抗肿瘤治疗的单抗、双抗和抗体偶联药物也进行了立项开发。小结作为我国原创新药领域的先行者，微芯生物经过二十年的行业深耕，成功开发出原创新药西达本胺和西格列他钠，这两款药物均已获批上市，同时还有多款潜力新药即将上市。近年来，随着药政改革的推进，以临床价值为导向、以患者为中心、差异化研发的理念逐渐深入人心。以微芯生物为代表，坚持做First-in-class的创新药企在激烈的竞争中展现出独特的优势。仅分析性内容，不构成任何投资建议来源 | 博药（药智网获取授权转载）撰稿 | 森林责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信） 阅读原文，是受欢迎的文章哦

EDMONTON, Alberta--(BUSINESS WIRE)-- Aurinia Pharmaceuticals Inc. (NASDAQ: AUPH) (Aurinia or the Company) today announced that full results from the Phase 3, double-blind, placebo-controlled AURORA 2 extension study were published online in Arthritis & Rheumatology, the official peer-reviewed journal of the American College of Rheumatology. As part of the AURORA Clinical Program, the AURORA 2 extension study assessed the long-term safety and tolerability of LUPKYNIS® (voclosporin), compared with placebo, in combination with mycophenolate mofetil and low-dose glucocorticoids, to treat active lupus nephritis (LN) in adult patients who completed one year of treatment in the Phase 3 AURORA 1 clinical trial. Voclosporin was well tolerated with no new or worsening safety signals in the extension study. Clinical efficacy over three years of treatment was maintained, as observed by maintenance of urine protein creatinine ratio (UPCR) reductions, sustained complete renal response (CRR) and preserved kidney function, suggesting a positive benefit-risk pro voclosporin in LN patients. “Proteinuria, a defining part of the characterization of chronic kidney disease, often precedes a decline in kidney function and is associated with progression to kidney failure. Reductions in proteinuria are critical for slowing or stopping progression to end-stage kidney disease and improving long-term outcomes for LN patients. Notably, in this extension study, kidney preservation, sustained renal response, and reductions in steroid use were achieved with voclosporin. These findings demonstrate the critical importance of voclosporin in the management of LN to improve patient outcomes,” said lead study author Amit Saxena, MD, Division of Rheumatology, New York University Grossman School of Medicine. Estimated glomerular filtration rate (eGFR), an important measurement of kidney function, remained stable throughout the extension study. The slope of the change in eGFR over the extension study period at month 36 demonstrated kidney function preservation in the voclosporin group (-0.2 mL/min/1.73m2), compared with a decline in function after one year in the control group (-5.4 mL/min/1.73m2). There was a significant increase in achievement of CRR in LN patients treated with voclosporin, compared to patients in the control group, at nearly every time point in the AURORA Clinical Program. At month 12, CRR occurred in 52.6% of patients who received voclosporin, compared to 34.0% in the control group, largely driven by achieving a proteinuria reduction in UPCR to ≤0.5 mg/mg. At month 36, CRR occurred in 50.9% of patients who received voclosporin, compared to 39.0% of patients in the control group. CRR was defined as UPCR of ≤0.5 mg/mg, eGFR ≥60 ml/min/1.73 m2 or no confirmed decrease from pretreatment baseline in eGFR of >20%, no rescue medication received for LN, and not receiving more than 10 mg of glucocorticoids for ≥3 consecutive days or for ≥7 days in total during the eight weeks prior to renal response assessment. These results were achieved with most patients in both groups (>75%) maintaining glucocorticoid tapering throughout the study and receiving doses of ≤2.5 mg/day at the end of the extension study. Of those who experienced adverse events (AEs) in the extension study, most were mild or moderate (86% in the voclosporin group vs. 81% in the control group). Across three years of treatment, infections were the most common type of AE (69.8% in the voclosporin group vs. 72.0% in the control group), with low rates of serious infections in both groups (12.9% in the voclosporin group vs. 17.0% in the control group). Most adverse events declined annually over the study period, with 86.1% of patients completing the two-year extension. “The results of this extension study reinforce the long-term safety and effectiveness of LUPKYNIS to stabilize kidney function in those diagnosed with LN, a debilitating, yet common complication that occurs in about half of people with lupus,” said Dr. Greg Keenan, Chief Medical Officer of Aurinia. “Together, AURA-LV, AURORA 1, and AURORA 2 represent one of the largest and longest placebo-controlled clinical programs evaluating the treatment of LN. We are proud of our sustained research in autoimmune diseases like lupus and remain committed to helping improve kidney health for people living with lupus nephritis.” About the AURORA Clinical Program In AURORA 1 (NCT03021499), a 12-month, phase 3, double-blind, randomized-controlled pivotal study, the efficacy and safety of voclosporin was compared with a control group in achieving CRR in patients with LN. AURORA 1 demonstrated the clinical superiority of voclosporin with mycophenolate mofetil (MMF) and low-dose glucocorticoids compared to MMF and low-dose glucocorticoids alone. Significantly more patients in the voclosporin group achieved a CRR at 52 weeks of treatment and did so significantly faster than those in the control group. The safety pro AURORA 1 was comparable between treatment groups, in line with previous studies; no new safety concerns were observed. Results from the completed Phase 3 randomized, double-blind, placebo-controlled, multicenter AURORA 1 study were published in The Lancet. AURORA 2 (NCT03597464) is a Phase 3, double-blind, extension study to assess the long-term safety and tolerability of voclosporin, in addition to MMF and low-dose glucocorticoids, for the treatment of patients with active LN. Patients who completed 12 months of treatment in the Phase 3 AURORA 1 study were eligible to enroll in the AURORA 2 extension study with the same randomized treatment of voclosporin or placebo, in combination with MMF (target dose of 2 g/day) and low-dose glucocorticoids (target dose of ≤2.5 mg/day), for an additional 24 months. A total of 216 LN patients continued into the extension study, with 116 patients in the voclosporin group and 100 patients in the control group; 90 and 78 patients, respectively, received 36 months of total treatment at the completion of the study. Study drug dose changes decreased over time. About Lupus Nephritis Lupus Nephritis is a serious manifestation of systemic lupus erythematosus (SLE), a chronic and complex autoimmune disease. About 200,000-300,000 people live with SLE in the U.S., and about one-third of these people are diagnosed with lupus nephritis at the time of their SLE diagnosis. About 50 percent of all people with SLE may develop lupus nephritis. If poorly controlled, lupus nephritis can lead to permanent and irreversible tissue damage within the kidney. Black and Asian people with SLE are four times more likely to develop lupus nephritis and Hispanic people are approximately twice as likely to develop the disease, compared to White people with SLE. Black and Hispanic people with SLE also tend to develop lupus nephritis earlier and have worse outcomes, compared to White people with SLE. About LUPKYNIS® LUPKYNIS® is the first U.S. Food and Drug Administration and European Commission-approved oral medicine for the treatment of adult patients with active LN. LUPKYNIS is a novel, structurally modified calcineurin inhibitor (CNI) with a dual mechanism of action, acting as an immunosuppressant through inhibition of T-cell activation and cytokine production and promoting podocyte stability in the kidney. The recommended starting dose of LUPKYNIS is three capsules twice daily with no requirement for serum drug monitoring. Dose modifications can be made based on Aurinia’s proprietary personalized eGFR-based dosing protocol. Boxed Warning, warnings, and precautions for LUPKYNIS are consistent with those of other CNI-immunosuppressive treatments. About Aurinia Aurinia Pharmaceuticals is a fully integrated biopharmaceutical company focused on delivering therapies to treat targeted patient populations with high unmet medical needs that are impacted by autoimmune, kidney and rare diseases. In January 2021, the Company introduced LUPKYNIS® (voclosporin), the first FDA-approved oral therapy dedicated to the treatment of adult patients with active lupus nephritis. The Company’s head office is in Edmonton, Alberta, its U.S. commercial office is in Rockville, Maryland. The Company focuses its development efforts globally. INDICATION AND IMPORTANT SAFETY INFORMATION INDICATIONS LUPKYNIS® is indicated in combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active LN. Limitations of Use: Safety and efficacy of LUPKYNIS have not been established in combination with cyclophosphamide. Use of LUPKYNIS is not recommended in this situation. IMPORTANT SAFETY INFORMATION BOXED WARNINGS: MALIGNANCIES AND SERIOUS INFECTIONS Increased risk for developing malignancies and serious infections with LUPKYNIS or other immunosuppressants that may lead to hospitalization or death. CONTRAINDICATIONS LUPKYNIS is contraindicated in patients taking strong CYP3A4 inhibitors because of the increased risk of acute and/or chronic nephrotoxicity, and in patients who have had a serious/severe hypersensitivity reaction to LUPKYNIS or its excipients. WARNINGS AND PRECAUTIONS Lymphoma and Other Malignancies: Immunosuppressants, including LUPKYNIS, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to increasing doses and duration of immunosuppression rather than to the use of any specific agent. Serious Infections: Immunosuppressants, including LUPKYNIS, increase the risk of developing bacterial, viral, fungal, and protozoal infections (including opportunistic infections), which may lead to serious, including fatal, outcomes. Nephrotoxicity: LUPKYNIS, like other CNIs, may cause acute and/or chronic nephrotoxicity. The risk is increased when CNIs are concomitantly administered with drugs associated with nephrotoxicity. Hypertension: Hypertension is a common adverse reaction of LUPKYNIS therapy and may require antihypertensive therapy. Neurotoxicity: LUPKYNIS, like other CNIs, may cause a spectrum of neurotoxicities: severe include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremor, paresthesia, headache, and changes in mental status and/or motor and sensory functions. Hyperkalemia: Hyperkalemia, which may be serious and require treatment, has been reported with CNIs, including LUPKYNIS. Concomitant use of agents associated with hyperkalemia may increase the risk for hyperkalemia. QTc Prolongation: LUPKYNIS prolongs the QTc interval in a dose-dependent manner when dosed higher than the recommended lupus nephritis therapeutic dose. The use of LUPKYNIS in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongation. Immunizations: Avoid the use of live attenuated vaccines during treatment with LUPKYNIS. Inactivated vaccines noted to be safe for administration may not be sufficiently immunogenic during treatment with LUPKYNIS. Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with another CNI immunosuppressant. If PRCA is diagnosed, consider discontinuation of LUPKYNIS. Drug-Drug Interactions: Avoid co-administration of LUPKYNIS and strong CYP3A4 inhibitors or with strong or moderate CYP3A4 inducers. Reduce LUPKYNIS dosage when co-administered with moderate CYP3A4 inhibitors. Reduce dosage of certain P-gp substrates with narrow therapeutic windows when co-administered. ADVERSE REACTIONS The most common adverse reactions (>3%) were glomerular filtration rate decreased, hypertension, diarrhea, headache, anemia, cough, urinary tract infection, abdominal pain upper, dyspepsia, alopecia, renal impairment, abdominal pain, mouth ulceration, fatigue, tremor, acute kidney injury, and decreased appetite. SPECIFIC POPULATIONS Pregnancy/Lactation: May cause fetal harm. Advise not to breastfeed. Renal Impairment: Not recommended in patients with baseline eGFR ≤45 mL/min/1.73 m2 unless benefit exceeds risk. Severe renal impairment: Reduce LUPKYNIS dose. Mild and Moderate Hepatic Impairment: Reduce LUPKYNIS dose. Severe hepatic impairment: Avoid LUPKYNIS use. Please see Prescribing Information, including Boxed Warning, and Medication Guide for LUPKYNIS. References: Saxena A., Ginzler E., Gibson K., Satirapoj B., Santillán A., Levchenko O., Navarra S., Atsumi T., Yasuda S., Chavez-Perez N., Arriens C., Parikh S., Caster D., Birardi V., Randhawa S., Lisk L., Huizinga R., Teng O. (2023), Safety and Efficacy of Long-Term Voclosporin Treatment for Lupus Nephritis in The Phase 3 AURORA 2 Clinical Trial. Arthritis Rheumatol. Accepted Author Manuscript:

来自日本熊本大学等机构的科学家们通过研究发现，一类能表达ROR1的部分EMT样细胞亚群或能促进胰腺癌和过度增殖并导致癌症转移。 如今在癌症治疗中，肿瘤启动细胞（Tumor-initiating cells）或癌症干细胞受到了科学家们越来越多的关注，因为其能在体内“游走”并通过转移在机体其它位点引发癌变肿瘤，这些细胞还会对化疗产生一定的耐受性，胰腺导管腺癌（PDAC，Pancreatic ductal adenocarcinoma）就是一种预后较差的癌症类型。转移性的问题在这类癌症中尤为突出，尽管肿瘤启动细胞参与到了某些癌症的疾病进展过程中，但其在胰腺腺癌中的具体作用、独特特征以及作用背后的信号通路，目前研究人员并不清楚，而在PDAC中根除这些细胞是否能带来任何治疗效益，目前研究人员也并不清楚。 此前研究结果表明，分散在肿瘤中的上皮-间质转化（EMT，epithelial–mesenchymal transition）样细胞或许具有转移和致癌能力，因此诸如EMT细胞群或许有望作为PDAC中肿瘤发生的良好候选细胞，受体酪氨酸激酶（RTKs，Receptor tyrosine kinases）是一类特殊的细胞表面标志物，其异常激活会引发癌症不断进展，其中，ROR1是一种已知会参与到多种人类癌症中的RTK。近日，一篇发表在国际杂志The EMBO Journal上题为“YAP/BRD4‐controlled ROR1 promotes tumor‐initiating cells and hyperproliferation in pancreatic cancer”的研究报告中，来自日本熊本大学等机构的科学家们通过研究发现，一类能表达ROR1的部分EMT样细胞亚群或能促进胰腺癌和过度增殖并导致癌症转移。 科学家发现一种能帮助识别胰腺癌中肿瘤启动细胞的特殊细胞表面标志物。 图片来源：The EMBO Journal (2023). DOI:10.15252/embj.2022112614 研究者Masaya Yamazaki说道，我们想通过研究来找出肿瘤启动细胞作为癌芽（cancer buds）发生的机制，从而就能设计出新型的抗癌药物，因此，我们首先要在单细胞水平上调查PDAC中的细胞多样性。文章中，研究人员试图通过结合多种技术来识别肿瘤启动细胞，包括单细胞RNA测序技术以及使用人类PDAC异种移植物（即将人类癌变组织移植到小鼠体内）。 研究人员发现，当移植到小鼠体内后，具有高水平ROR1的胰腺细胞要比携带低水平ROR1的胰腺细胞而言更加高效地产生癌变组织，而且，ROR1水平较高的细胞在转移性病灶中更为丰富，这就表明，这些ROR1高水平的细胞或许就是癌症发生转移的起源。此外，ROR1高水平的细胞或许会在患者化疗后促进癌症复发，有意思的是，在化疗期间抑制ROR1的表达会减少患者癌症的复发率，研究者Yamazaki博士表示，ROR1是胰腺肿瘤组织中部分EMT样细胞的特征性标志物，高表达的ROR1能驱动致瘤性的发生、肿瘤内的异质性以及肿瘤的进展。 随后研究人员进一步在分子水平上阐明了ROR1所扮演的关键角色，从而就证实了ROR1能诱导蛋白极光激酶 B（Aurora kinase B）的表达，后者已知能加速肿瘤的增殖；此外研究人员还发现，Yes相关蛋白（YAP）/含溴结构域4（BRD4）-轴或能作为参与ROR1基因表达调节的特殊因子，基于这些研究结果，研究人员提出了利用BET抑制剂或能作为靶向作用ROR1的新型治疗性手段。 研究人员相信，他们的研究发现或能为改进胰腺癌疗法策略和未来的药物发现奠定一定的基础，这些研究结果也表明了研究ROR1的重要性，这样研究人员就能了解其在PDAC和其它癌症发病机制中所扮演的关键角色。综上，本文研究结果揭示了ROR1高表达的细胞作为肿瘤启动细胞的关键作用，同时也阐明了ROR1在PDAC进展过程中的功能重要性，这就凸显出了其治疗靶向特性。（生物谷Bioon.com） 原始出处： Masaya Yamazaki，Shinjiro Hino，Shingo Usuki, et al. YAP/BRD4‐controlled ROR1 promotes tumor‐initiating cells and hyperproliferation in pancreatic cancer, The EMBO Journal (2023). DOI:10.15252/embj.2022112614