A Proof-of-Concept, Open-Label Study Evaluating the Safety and Tolerability of Cilofexor in Subjects With Primary Sclerosing Cholangitis (PSC) and Compensated Cirrhosis

The primary objective of this study is to assess the safety and tolerability of escalating doses of cilofexor (CILO) in participants with primary sclerosing cholangitis (PSC) and compensated cirrhosis.

开始日期2019-10-17

申办/合作机构

Gilead Sciences, Inc.

NCT03987074 / Completed临床2期

A Proof of Concept, Open-Label Study Evaluating the Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Subjects With Nonalcoholic Steatohepatitis (NASH)

The primary objective of this study is to evaluate the safety and tolerability of study drug(s) in participants with nonalcoholic steatohepatitis (NASH).

开始日期2019-07-29

申办/合作机构

Gilead Sciences, Inc.

[+1]

ACTRN12619000655145 / Completed临床1期

A Phase 1 Open-Label, Parallel-Group, Two-Treatment, Single-Dose Study to Evaluate the Pharmacokinetics of GS-9674 and GS-0976 in Subjects with Normal Renal Function and Severe Renal Impairment

开始日期2019-07-24

申办/合作机构

Gilead Sciences, Inc.

100 项与 Cilofexor tromethamine 相关的临床结果

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100 项与 Cilofexor tromethamine 相关的转化医学

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100 项与 Cilofexor tromethamine 相关的专利（医药）

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项与 Cilofexor tromethamine 相关的文献（医药）

2024-01-01·JHEP reports : innovation in hepatology

Combined inhibition of bile salt synthesis and intestinal uptake reduces cholestatic liver damage and colonic bile salts in mice

Article

作者: van de Graaf, Stan F J ; van Dasselaar, Rychon D J ; Oude Elferink, Ronald P J ; Beuers, Ulrich ; Nijmeijer, Bart A ; Bolt, Isabelle ; Kunst, Roni F

Background & Aims:

Intestine-restricted inhibitors of the apical sodium-dependent bile acid transporter (ASBT, or ileal bile acid transporter) are approved as treatment for several inheritable forms of cholestasis but are also associated with abdominal complaints and diarrhoea. Furthermore, blocking ASBT as a single therapeutic approach may be less effective in moderate to severe cholestasis. We hypothesised that interventions that lower hepatic bile salt synthesis in addition to intestinal bile salt uptake inhibition provide added therapeutic benefit in the treatment of cholestatic disorders. Here, we test combination therapies of intestinal ASBT inhibition together with obeticholic acid (OCA), cilofexor, and the non-tumorigenic fibroblast growth factor 15 (Fgf15)/fibroblast growth factor 19 (FGF19) analogue aldafermin in a mouse model of cholestasis.

Methods:

Wild-type male C57Bl6J/OlaHsd mice were fed a 0.05% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and received daily oral gavage with 10 mg/kg OCA, 30 mg/kg cilofexor, 10 mg/kg ASBT inhibitor (Linerixibat; ASBTi), or a combination. Alternatively, wild-type male C57Bl6J/OlaHsd mice were injected with adeno-associated virus vector serotype 8 (AAV8) to express aldafermin, to repress bile salt synthesis, or to control AAV8. During a 3-week 0.05% DDC diet, mice received daily oral gavage with 10 mg/kg ASBTi or placebo control.

Results:

Combination therapy of OCA, cilofexor, or aldafermin with ASBTi effectively reduced faecal bile salt excretion. Compared with ASBTi monotherapy, aldafermin + ASBTi further lowered plasma bile salt levels. Cilofexor + ASBTi and aldafermin + ASBTi treatment reduced plasma alanine transaminase and aspartate transaminase levels and fibrotic liver immunohistochemistry stainings. The reduction in inflammation and fibrogenesis in mice treated with cilofexor + ASBTi or aldafermin + ASBTi was confirmed by gene expression analysis.

Conclusions:

Combining pharmacological intestinal bile salt uptake inhibition with repression of bile salt synthesis may form an effective treatment strategy to reduce liver injury while dampening the ASBTi-induced colonic bile salt load.

Impact and Implications:

Combined treatment of intestinal ASBT inhibition with repression of bile salt synthesis by farnesoid X receptor agonism (using either obeticholic acid or cilofexor) or by expression of aldafermin ameliorates liver damage in cholestatic mice. In addition, compared with ASBT inhibitor monotherapy, combination treatments lower colonic bile salt load.

2023-11-01·JHEP reports : innovation in hepatology

Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis

Article

作者: Minto, Wesley ; Hollenback, David ; Budas, Grant ; Gupta, Ruchi ; Fuchs, Claudia D ; Trauner, Michael ; Scharnagl, Hubert ; Liles, John T ; Stojakovic, Tatjana ; Sroda, Natalie

Background & Aims:

The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteracting features of cholestatic liver injury by evaluating its efficacy and mechanisms in the Mdr2/Abcb4 knockout (^-/-) mouse model of sclerosing cholangitis.

Methods:

FVB/N wild-type and Mdr2^-/- or BALB/c wild-type and Mdr2^-/- mice were treated with 0, 10, 30 or 90 mg/kg cilofexor by gavage every 24 h for 10 weeks. Serum biochemistry, gene expression profile, hydroxyproline content, and picrosirius red and F4/80 immunostaining, were investigated. Bile flow, biliary bicarbonate and BA output, and hepatic BA profile, were assessed.

Results:

Cilofexor treatment improved serum levels of aspartate aminotransferase, alkaline phosphatase as well as BAs in Mdr2^-/- animals. Hepatic fibrosis was improved, as reflected by the reduced picrosirius red-positive area and hydroxyproline content in liver sections of cilofexor-treated Mdr2^-/- mice. Intrahepatic BA concentrations were lowered in cilofexor-treated Mdr2^-/- mice, while hepatobiliary bile flow and bicarbonate output were increased.

Conclusion:

Collectively the current data show that cilofexor treatment improves cholestatic liver injury and decreases hepatic fibrosis in the Mdr2^-/- mouse model of sclerosing cholangitis.

Impact and implications:

Treatment with cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, improved histological features of sclerosing cholangitis, cholestasis and hepatic fibrosis in the Mdr2^-/- mouse model. These findings indicate, that pharmacological stimulation of intestinal FXR-mediated gut-liver signaling, via fibroblast growth factor 15 (thereby reducing bile acid synthesis), may be sufficient to attenuate cholestatic liver injury in the Mdr2^-/- mouse model of sclerosing cholangitis, thus arguing for potential therapeutic properties of cilofexor in cholestatic liver diseases.

2023-09-01·Journal of clinical pharmacology

Effect of Hepatic Impairment on the Pharmacokinetics and Pharmacodynamics of Cilofexor, a Selective Nonsteroidal Farnesoid X Receptor Agonist.

Article

作者: Nelson, Cara ; Yue, Mun Sang ; Hsueh, Chia-Hsiang ; Billin, Andrew N ; Othman, Ahmed A ; Xiao, Deqing ; Watkins, Timothy R ; Younis, Islam R

Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child-Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP-A or B; 10 mg for CP-C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration-time curve was 76%, 2.5-fold, and 6.3-fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration-time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2-fold, and 3.16-fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α-hydroxy-4-cholesten-3-one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor-related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI.

项与 Cilofexor tromethamine 相关的新闻（医药）

2024-05-23

·研发客

又一百亿美元赛道，GLP-1和小核酸正在抢跑 | 行业观察

// 首款MASH药物已经上市，但我们发现GLP-1类药物、小核酸疗法在MASH领域已经展现出活跃的势头，包括探索药物的联用。弗若斯特沙利文预计，MASH全球市场规模将在2030年突破300亿美元。初步数据显示，GLP-1R/GIPR/GCGR三靶点药物retatrutide能将患者的平均相对肝脏脂肪含量减少超过80%，而首款MASH药物resmetirom只有51%。有业内人士甚至认为，未来GLP-1（包含GLP-1/FGF21在内的双靶点和三靶点）将会抢占更多MASH市场。小核酸加入竞争阵营，则是瞄准MASH晚期即F4阶段的肝硬化、肝癌患者，从遗传因素角度找出晚期MASH的致病基因，进行针对性和精准化开发，实现逆转肝纤维化的可能性。例如PNPLA3基因分型就与肝硬化发病高度相关。在GLP-1类药物和小核酸之外，各类THR-β、FGF21、FXR、PPAR靶点仍然在MASH领域中寻找更多可能性。国内进入临床阶段的MASH药物较多聚焦在THR-β靶点，也有一些企业另辟蹊径开发同类首创产品。如，雅创医药的非胆汁酸结构的FXR激动剂HPG1860，2a期临床暂未观察到LDL-C升高。君圣泰医药的HTD1801由活性组分小檗碱和熊去氧胆酸盐组成，是全球首创的新分子实体。众生睿创的ZSP1601是国内首个获批临床治疗MASH的泛磷酸二酯酶（pan-PDE）抑制剂。来自GLP-1的压力：联合用药最早涉猎MASH的GLP-1是司美格鲁肽，也是全球进展最快的产品，已启动3期临床。而后再陆续延伸到GLP-1双靶点和三靶点。从具体数据看，GLP-1的跨界确实给其他MASH药物带来了压力。如，默沙东的10mg剂量efinopegdutide在用药24周后，肝脏脂肪含量（LFC）相对于基线降幅达72.7%；Altimmune的pemvidutide在2.4mg剂量在24周的LFC相对减少量达到76.4%。而resmetirom在治疗52周后，患者肝脏脂肪水平平均降低51%。efinopegdutide和pemvidutide均是GLP-1R/GCGR双重激动剂，上述结果也充分证明了GLP-1双靶点在MASH的治疗潜力。再看GLP-1R/GIPR/GCGR三靶点retatrutide，24周时，8mg和12mg剂量组的肝脏脂肪相对减少分别达到了81.4%和82.4%。单从LFC的数据看，GLP-1三靶点大于80%的减脂率显示出其优于双靶点及其他MASH靶点药物的治疗结果。但仅有LFC数据优势还不够，GLP-1还需要从FDA建议的临床终点中证明疗效。据FDA 2018年发布的指南推荐，MASH确证性研究的替代终点包括：肝组织纤维化改善≥1且MASH不恶化、MASH消退（MASH resolution）且肝纤维化未恶化。已公布的临床数据中，司美格鲁肽在MASH消退中显示出积极结果，但纤维化改善结果不具备统计学意义。礼来的替尔泊肽（tirzepatide）在2期临床中也达到了MASH消除且纤维化未恶化终点，最高剂量有73.9%患者获益，但尚未公布纤维化改善数据。其他GLP-1的双靶点和三靶点药物还要期待更进一步的临床结果。除了单药GLP-1多靶点的进一步优化，企业也尝试通过联合用药进一步改善疗效。如国内企业中，诚益生物在探索THR-β和GLP-1的联合疗法。众生睿创联合创始人兼总裁陈小新表示，众生睿创将来也会考虑将GLP-1分子与PDE抑制剂ZSP1601做联合治疗。海外企业的GLP-1联合治疗组合中，进展较快的有3个，分别是司美格鲁肽+efruxifermin、司美格鲁肽+firsocostat+cilofexor以及NNC0194-0499/司美格鲁肽复方制剂。其中联合的efruxifermin、NNC0194-0499均是成纤维细胞生长因子21（FGF21）类似物。陈小新解释道，GLP-1、FGF21从代谢角度改善MASH，同时FGF21展现了强大抗肝纤维化能力，GLP-1+FGF21是代谢和纤维化改善的结合。从目前已公布的数据中能看到，FGF21在改善肝脏纤维化中疗效是最优的。Akero公司最新公布的2b期HARMONY研究显示，efruxifermin单药治疗96周后，最高剂量50mg中患者纤维化改善≥1级且MASH不恶化的比例达75%，且纤维化改善≥2级的比例达到36%。且efruxifermin+GLP-1联合治疗已有积极数据公布，2b期研究显示，12周后相对肝脂肪含量平均降幅达65%，而GLP-1单药治疗降幅仅为10%；12周后，联用组有88%的受试者肝脏脂肪含量正常（≤5%），单药组仅有10%。相比司美格鲁肽单药，联合治疗显示出更优的治疗效果。“GLP-1类代谢机制药物能阻止MASH向后期阶段转归。而且GLP-1在减重阶段的广泛使用，就可能预防了MASH的发生，基于GLP-1的多靶点激动剂如GLP-1/FGF21、GLP/GIP、GLP/GCG明显有更好的治疗效果，对其他通路的MASH药物而言，将是降维打击。”陈小新认为。同时陈小新也指出了代谢机制药物暂时无法解决的问题，“MASH进展到F4期（肝硬化阶段）想要逆转肝纤维化非常困难，目前为止还没有药物能够解决，仅FGF21激动剂efruxifermin还有一线希望。”既往也有多项研究在F4期折戟的案例。如，奥贝胆酸的治疗MASH代偿期肝硬化（F4）患者的3期REVERSE研究未达到肝纤维化组织学改善≥1级且NASH没有恶化的主要终点。吉利德的ASK1抑制剂selonsertib在针对MASH F4患者治疗的3期stellar-4临床研究未达主要终点。吉利德开展的另一项cilofexor+firsocostat的2期研究，对F3-F4期的患者，未达到改善纤维化的主要终点。小核酸：挑战终极难关当其他靶点的小分子或抗体遭遇F4阶段挑战时，小核酸或能另辟蹊径提供不一样的治疗思路。今年初，瑞博生物与勃林格殷格翰达成治疗MASH的小核酸疗法合作，总金额超20亿美元。据瑞博生物联席CEO、全球研发总裁甘黎明透露，BI已有针对早期MASH的GCGR/GLP-1R双靶点抑制剂survodutide，而与瑞博生物合作，是希望开发针对晚期MASH及其并发症的小核酸药物。为什么小核酸有治疗晚期MASH的可能性？小核酸药物可以特异性靶向肝细胞内、而小分子和抗体无法突破的精准靶标，甘黎明介绍道，现有其他MASH药物的靶点和机制都是减缓肝脂肪和纤维化进展，没有从遗传因子角度考虑。而小核酸药物是找出表达肝纤维化进展的致病遗传基因，抑制基因异常表达，阻止或逆转肝纤维化，达到实质性治疗目的。目前国内外临床上应用较多、增加MASH风险的遗传因子有HSD17B13、PNPLA3。以PNPLA3为例，多项研究已证明PNPLA3（patatin样磷脂酶域3）的I148M变体是肝硬化的重要风险基因，与肝硬化发病率较高相关。因而靶向PNPLA3基因分型的小核酸药物，能够特异性识别和治疗PNPLA3致病MASH患者。“这就类似于肿瘤中针对性基因突变表达的药物开发，只针对该基因突变如EGFR表达的癌症人群。”甘黎明解释道。例如靶向PNPLA3小核酸疗法，其研究对象就是PNPLA3 148M风险等位基因携带的MASH患者。国内企业中，瑞博生物已开发两款临床前MASH产品RBD1073和RBD5083，其中RBD1073靶向HSD17B13。维亚臻生物已将HSD17B13靶向的siRNA VSA006推进至治疗MASH的2期临床阶段。舶望制药管线中有3款针对MASH的临床前siRNA，分别靶向PNPLA3、HSD17B13和CIDEB。放眼海外，MNC正通过合作的方式不断加码MASH小核酸领域，如Alnylam与Regeneron、Arrowhead与GSK、Ionis与阿斯利康的多笔合作交易。在小核酸治疗MASH赛道中，反义寡核苷酸（ASO）和小分子干扰RNA（siRNA）的临床进展似乎不分上下。目前仅有Ionis的ASO疗法ION224公布了2期结果，治疗51周后，90mg和120mg两个剂量组都达到了MASH组织学改善且纤维化未恶化的主要终点。但相比ASO，甘黎明更看好siRNA在MASH赛道中的地位。他表示，ION224靶向二酰基甘油酰基转移酶2（DGAT2），是通过抑制DGAT2降低肝脏甘油三酯以改善MASH，其治疗机制和适应症人群与GLP-1类似，而且其对早期肝纤维化的潜在影响主要是间接的。ASO现在能做到一月一次的给药周期，而siRNA的治疗周期是至少三个月到半年。“这样对于像MASH这种慢性病，siRNA会显著提高患者依从性。此外，ASO有血小板减少等安全性的疑问，而在siRNA中还未观察到类似风险。”甘黎明说。临床开发失败案例的启示再回头看那些MASH临床开发失败的药物，陈小新表示，部分产品失败是因为它们有效性不够导致风险获益比不足以支持其获批。例如奥贝胆酸，高剂量组的纤维化改善≥1级且MASH不恶化的比例为22.4%，虽具有统计学意义，但结合严重瘙痒、升高低密度脂蛋白胆固醇（LDL-C）等不良反应，最终FDA拒绝了其上市之路。再看另一款PPARα/δ激动剂elafibranor的结果，主要终点MASH改善且肝纤维化无恶化中，安慰剂组数据从2期的11%上升到3期的14.7%，即使给药组有效性达到19.2%，但异常安慰剂效应使临床结果不具备统计学意义，最终试验失败。从奥贝胆酸和elafibranor失败可总结出resmetirom能成功获批的原因。resmetirom的两个关键替代终点——纤维化改善≥1级且MASH不恶化、MASH消退而且未出现肝纤维化恶化都达到统计学意义改善，且还有降低心血管风险潜力，LDL-C相比安慰剂组显著下降。所以即便药物在纤维化改善≥1级且MASH不恶化的主要终点比例只达到26%，有效性相比奥贝胆酸仅高出一点。“从风险获益比角度考量，resmetirom的临床结果足以支持其获批上市，”陈小新解释道，“我们分析了所有MASH成功或失败临床试验，在F2-F3患者人群中，在MASH消退这个终点上，安慰剂组应答率基本在11%左右，如果某个药物的应答率能够达到40%以上，3期临床结果大概率能够做出统计学意义的差异。”而resmetirom的获批只是起点，未来还有更多疗效超过resmetirom的药物相继出现。编辑 | 姚嘉yao.jia@PharmaDJ.com 总第2115期访问研发客网站可浏览更多文章www.PharmaDJ.com

临床3期临床结果基因疗法核酸药物

2024-03-06

·E药经理人

一款产品撑起百亿估值，40年首款新药将撞线！默沙东、BI、安进巨头“割据”，2024首个爆发的黄金领域

MASH研发，40年无新药获批，大到辉瑞、吉利徳，小到Intercept、Genfit，“先烈”无数。当有望成为首个上市产品的审评结果月底揭晓，无论“撞线”与否，都将点燃一场MNC间混战的烽火。撰文| Erin 石若萧编辑| 彡氜 Erin近期，生物技术公司Akero发布最新代谢功能障碍相关脂肪性肝炎（MASH）新药临床数据，股价大涨60%；同时，有望最先“撞线”MASH的产品（由Madrigal研发）resmetirom也将在本月迎来审评最后日期。2024年第一个爆发的黄金领域就此诞生。如果翻开他们的履历会发现，“大药”领域最终的结局都不是仅有Biotech单兵作战，Akero“背靠”安进，Madrigal脱胎于罗氏，另一家明星公司Zealand早早被BI预定，Viking也“期待”被大药企收购。此外，礼来、诺和诺德两巨头手握GLP-1在MASH领域一路过关斩将，开辟了新战场。MASH新药未到，大公司却已瓜分完领地。不出意外，MASH这片40年无新药获批的“无人之境”已成大家竞赛的新战场。也许，本月resmetirom的“撞线”结果将点燃第一场战役的烽火。安进“背书“，辉瑞投资的MASH明星40年没有新药上市，吉利德、辉瑞等MNC也曾在此碰壁，一系列标签让MASH新药的开发仿佛与制药界隔开了一条难以逾越的鸿沟。重重关卡下，也有诸多生物技术公司在研发之路上被迫“死亡”。但Akero Therapeutics不仅穿越了“死亡周期”，还跑在了行业前列，仅靠Efruxifermin这一款产品便撑起17亿美元（约122亿人民币）的估值。与其将Akero看作一家生物技术公司，不如将其视作专为开发Efruxifermin这款产品而诞生。Efruxifermin能够在MASH屡战屡败的新药研发史中没有致命性失败，靶向FGF21的作用机制是一方面，Akero的投入、专为其打造的团队，甚至是其“幕后大佬”安进的背景都是另一面的加分项。2017年初，风投机构Apple Tree Partners（ATP）和深耕代谢领域数十年的科学家Tim Rolph共同创立了Pippin Pharmaceuticals（Akero前身），并由ATP合伙人之一Jonathan Young担任联合创始人兼首席运营官，但当时仅仅确定了代谢和心血管这一方向，并没有任何的技术与产品。彼时，被证实在代谢领域有极大开发潜力的FGF21机制产品也被安进开发到了临床初期阶段。然而新药开发九死一生，数十年无新药诞生的MASH领域更是如此。Pippin需要首发产品，押注诸多新机制的安进也需要风险分担。或许是命运使然，2018年6月，Pippin从安进获得了当时还在开发早期的FGF21类似物AMG876（AKR-001，Efruxifermin），同时该公司也正式更名为Akero Therapeutics。值得注意的是，引进产品的当月，Akero就获得了Apple Tree Partners（ATP）、Atlas Venture、venBio Partners、Versant Ventures 四家专注在生命科学领域的投资机构领投的6500万美元A轮融资。这一融资似乎说明了Akero的早有打算。同年12月，Akero再次凭此拿到了数千万美元的B轮融资，ATP和Atlas同样参与其中，还获得了Janus Henderson Investors、Redmile Group、BVF Partners等十余家国外知名投资机构的青睐。有意思的是，为了引进AKR-001，Akero除了付给安500万美元的预付款外，还两次分给安进股份，两次累计占公司已发行股份总数高达10%。一系列动作，展示了MASH领域以Akero和安进为代表的开发者们的艰难和犹豫。正如Akero的目标也是既要保证AKR-001开发能得到更聚焦的资源，又不能承担完全的开发风险。有安进“背书”，加上一众投资机构加持，Akero为AKR-001招揽到了高配版的开发团队。科学家创始人Tim Rolph在Akero担任首席科学官，他曾就职于辉瑞，同样负责曾辉瑞的FGF21项目和代谢领域的开发。临床研究和医疗事务副总裁Reshma Shringarpure和原料药工艺开发副总裁Arindam Bose也都来自辉瑞。此外，该公司的总裁兼首席执行官Andrew Cheng曾在吉利徳的临床开发职位任职近20年，而首席开发官Kitty Yale、商业战略高级副总裁Patrick Lamy、开发运营副总裁Brittany de Temple也都来自吉利徳这家在MASH领域的早期探路者。可以看到，Akero的高管团队组建也是从临床开发和CMC角度出发，聚焦AKR-001产品再开发的意图更加明显。实际上，2018年Akero就与BI和Vetter Pharma达成合作，生产用于临床开发的原料药，并预计在该产品商业化后与这两家原料药供应商继续合作。这一合作让Akero聚焦资源开发AKR-001的目的更加明确。当然，MASH新药研发之难，Efruxifermin的开发进程也并非一帆风顺。Akero公司在2019年进行了IPO，并募资1.058亿美元，在2020年再次募资2.164 亿美元，两笔总额超3亿美元的募资几乎全用于Efruxifermin的临床开发。此外，在2022年，Akero还获得了来自辉瑞的2500万美元股权投资以及来自知名机构Hercules Capital的1亿美元贷款。然而，在2023年，IIb期SYMMETRY研究中期分析结果却显示第36周时，试验观察到了肝纤维化改善的主要终点趋势，但不具有统计学意义。这次失败不仅被写入了“2023年十大临床失败案例”之中，还让Akero股价大跌76%，一朝触底，直接跌至刚上市时的水平。不过，或许是对于自家产品机制的自信，也或是来自高配团队的底气，Akero公司不仅未被这次短暂的“失败”所打击，反而一鼓作气，于去年底启动了三期临床。终于，本次的96周最终数据显示出的超高响应率让市场重拾对Akero的信心，也让MASH新药开发在2024年再次成为业界关注的焦点。有意思的是，如果浏览Akero的财报，行业中频频谈及的“降本增效”字眼几乎没有出现，也是近几年以来制药行业少有的0大规模裁员、0现金流风险、0剥离资产的生物技术公司。而支撑它能够还算顺利的一路走来的因素也很明确：背靠大公司；组建专业团队；专注研发，“轻资产”策略，至今仅有56名员工；十年只聚焦一款产品开发。它也再次验证了“祛魅技术平台，聚焦核心产品”这一穿越周期策略的有效性。推荐阅读 * 20年老牌NASH先驱被收购！辉瑞、诺华、AZ、罗氏…TOP10药企多折戟，谁能率先突围研发黑洞？* 15:1！FDA推迟首个NASH药物上市，辉瑞、诺华、吉利德曾折戟，中国药企有望弯道超车？MNC瓜分地盘MASH疗法的开发相当艰巨。Intercept是失败者中最接近成功的一位，最终成为“先烈”。当时Intercept产品的Ⅱ期MASH数据曾一度让投资者追捧，股价上涨超过500%，然而却连续被FDA因使用替代终点、副作用风险太大等原因拒绝上市。在去年6月上市申请第二次遭拒后，Intercept决定停止MASH领域所有投资，并解雇了三分之一的员工，重新聚焦到了罕见病和感染性肝病领域。失意者还有许多：2019年，吉利德遭遇三次临床失败，selonsertib 、firsocostat、cilofexor 纷纷折戟；诺华与Conatus公司合作开发的emricasan未能通过中期临床试验；2020年，Genfit宣布elafibranor治疗NASH的III期临床试验失败；2021年和2022年，辉瑞相继放弃了PF-06835919和danuglipron；去年，阿斯利康决定终止开发GLP-1R/GCGR激动剂cotadutide……无数的失败也阻挡不了科学的进步。随着大量迎难而上的后来者不断冲击，MASH终于再次迎来了曙光。本月，连续多个成果涌现，除了得到积极数据的Akero Therapeutics之外，目前进度最靠前的是Madrigal公司的resmetirom，PDUFA日期为2024年3月14日，若成功获批，resmetirom将会成为第一款获得FDA批准的MASH药物。有意思的是，目前MASH领域的主要玩家虽然表面上都是小公司，背后却多少都有MNC的影子，毕竟研发实在太难，要是没点实力，真的撑不住。Akero Therapeutics的efruxifermin当初是从安进处引进，而Madrigal则和罗氏渊源颇深，创始人Rebecca Taub曾在罗氏的代谢研究小组承担领导职责。2008年，VIA Pharmaceuticals公司与罗氏签订了Resmetirom药物的合作开发协议，此后Taub离开罗氏，并从罗氏获得了该药物的许可，再将许可转让给了VIA Pharmaceuticals，经过多次权益变动后，Resmetirom才终于归属于Madrigal，并开始了临床Ⅰ期试验。研发里的一波三折让Madrigal也有找“大树”的想法。有消息称，Taub其实早在Resmetirom的II期临床取得结果之时就有意将其出售，但因为价格不理想而不了了之。至今，Madrigal仍是 2023年十大潜在并购标的之一。勃林格殷格翰（BI）是MASH领域的主要押注者之一，前者日前公布了与Zealand Pharma共同开发的GLP-1/Glucagon双受体双激动剂survodutide的新II期数据，表明其对MASH形成了统计学意义的改善。基于结果，BI表示survodutide有望成为治疗MASH的潜在最佳药物。消息传出后，Zealand Pharma的股价上扬了25%。不仅如此，年初，勃林格殷格翰还与瑞博生物达成了一笔总交易金额超20亿美元的合作，共同开发治疗MASH的小核酸创新疗法。默沙东在多年前通过一笔收购获得了如今进度靠前的产品。2023年，在EASL年会上默沙东公布了其MK-6024（Efinopegdutide）的Ⅱa期结果：与GLP-1激动剂活性对照相比，其可显著减少患者肝脏脂肪，该组患者24周后的肝脏脂肪水平降低72.7%。Efinopegdutide来自于默沙东对于韩美制药的收购。前不久因GLP-1药物二期临床数据优异，引发股价大涨的Viking Therapeutic同样也在MASH领域有所布局，其四款核心在研药物中的VK2809于2023年发布了IIb期临床（VOYAGE研究）积极顶线数据，显示治疗12周可以显著降低受试者肝脂肪含量，最高平均相对降幅达到51.7%。不少业内人士分析，Viking Therapeutic最终的命运多半是被MNC收购。毕竟为了规避未来竞争，礼来与诺和诺德都存在收购动机，辉瑞等企业也有充足动力凭借收购实现“弯道超车”。事实上，就在GLP-1药物Ⅱ期临床数据公布前，礼来已提出以每股40至50美元的价格收购Viking，但后者认为报价远远不够，才决定公布数据，自抬身价。此外，GLP-1“双姝”礼来与诺和诺德也都在努力突破MASH适应证，并且都表现出了相当的治疗潜力：上个月礼来公布的四季度财报中提到，替尔泊肽在治疗MASH的Ⅱ期试验中显示出了积极结果；诺和诺德方面则早在2016年就开始了司美格鲁肽针对MASH的临床试验，现在已经处于临床Ⅲ期，临床Ⅱ期数据显示最高剂量治疗组66.7%的患者症状得到消除。可以预见，如今美国生物医药投资市场正在回暖，当“背靠”安进的Akero和早被BI预定的Zealand取得临床积极数据，而Madrigal一旦率先“撞线”，MASH领域的并购风暴将再度被点燃，溢价估值、独角兽被挖掘，2024年第一场创新药狂欢或将属于MASH。回复“2024”，了解电子期刊详情精彩推荐CM10 | 集采 | 国谈 | 医保动态 | 药审 | 人才 | 薪资 | 榜单 | CAR-T | PD-1 | mRNA | 单抗 | 商业化 | 国际化｜猎药人系列专题 | 出海启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 医药界·E药经理人 | 中国医药手册创新100强榜单 | 恒瑞 | 中国生物制药 | 百济 | 石药 | 信达 | 君实 | 复宏汉霖｜翰森 | 康方生物 | 上海医药 | 和黄医药 | 东阳光药 | 荣昌 | 亚盛医药 | 齐鲁制药 | 康宁杰瑞 | 贝达药业 | 微芯生物 | 复星医药｜再鼎医药｜亚虹医药跨国药企50强榜单 | 辉瑞 | 艾伯维 | 诺华 | 强生 | 罗氏 | BMS | 默克 | 赛诺菲 | AZ | GSK | 武田 | 吉利德科学 | 礼来 | 安进 | 诺和诺德 | 拜耳 | 莫德纳 | BI | 晖致 | 再生元

并购

2024-02-12

·MedCity News

Gilead’s $4.3B CymaBay Acquisition Adds Liver Disease Drug Under FDA Review

Gilead Sciences is acquiring biotech company CymaBay Therapeutics in a $4.3 billion deal that comes with a drug candidate currently under FDA review in a rare liver disease with few treatments. According to deal terms announced Monday, Gilead will pay $32.50 cash for each share of CymaBay. That price is a 27% premium to CymaBay’s closing stock price on Friday. The acquisition marks a comeback for the company and its drug, which just a few years ago faced an uncertain future amid safety questions. The main asset of CymaBay is seladelpar, a drug that the Newark, California-based company has developed for treating primary biliary cholangitis (PBC), a rare and progressive autoimmune condition that destroys the bile ducts of the liver. But this small molecule was at one time among the leading drug candidates for nonalcoholic steatohepatitis (NASH), a fatty liver disease that has no FDA-approved treatments. In 2019, a safety signal led CymaBay to stop a mid-stage test of seladelpar in NASH as well as a recently started study in primary sclerosing cholangitis, another chronic liver disorder. The FDA subsequently placed a formal clinical hold on the drug. The hold also stalled the development of the drug in PBC. The FDA cleared the company to resume testing of the drug in 2020, but CymaBay elected to continue development only in PBC. PBC is a chronic disorder that mainly affects women over the age of 40, impairing liver function. Common early symptoms include severe pruritus (itching) and fatigue. PBC can progress to cirrhosis and liver failure. The first-line drug treatment for PBC is ursodeoxycholic acid, or ursodiol, an old drug for dissolving gallstones that in 1996 won an additional approval as a treatment for PBC. The Intercept Pharmaceuticals drug Ocaliva was approved in 2016 as a second-line therapy for PBC. Intercept, which was acquired late last year by Italian company Alfasigma, reported $240.4 million in sales for the drug in the nine months ended Sept. 30, 2023. CymaBay’s seladelpar is a small molecule designed to bind to and activate peroxisome proliferator activated receptor delta (PPAR delta), a receptor that regulates genes involved in the synthesis of bile acids, metabolism, inflammation, and fibrosis. In its placebo-controlled Phase 3 clinical trial, results showed treatment with the drug led to statistically significant normalization of enzymes indicative of liver disease as well as improvement in pruritus. Late last year, CymaBay submitted a new drug application seeking approval of seladelpar as a treatment for patients who are inadequate responders to or intolerant of ursodiol. CymaBay announced Monday that the FDA will evaluate the application under priority review, setting an Aug. 14 target date for a regulatory decision. Gilead’s portfolio of liver disease drugs include the hepatitis B drugs Vemlidy and Viread as well as hepatitis C drug Harvoni. The Foster City, California-based drugmaker is also in the chase for NASH (now also called MASH, for metabolic associated steatohepatitis) with cilofexor and firsocostat, which are in Phase 2 testing as part of a combination treatment with Novo Nordisk’s semaglutide. “Building on the strong research and development work by the CymaBay team to date, we have the potential to address a significant unmet need for people living with PBC and expand on our existing broad range of transformational therapies,” Gilead Chairman and CEO Daniel O’Day said in a prepared statement. CymaBay licensed seladelpar from Johnson & Johnson in a 2006 deal. If it’s approved, J&J is in line to receive royalties from sales. The CymaBay pipeline also includes MBX-2982, a molecule in Phase 2a testing for treating hypoglycemia in patients with type 1 diabetes. In a note sent to investors, William Blair analyst Andy Hsieh wrote that the CymaBay acquisition validates the clinical performance and commercial potential of seladelpar in PBC. He called the acquisition “poetic closure” for the company following the molecule’s previous clinical trial setbacks “We commend management’s resilience and persistence that ultimately led to seladelpar demonstrating the best-in-class clinical profile in PBC, and we expect the drug to benefit thousands of patients living with PBC as soon as later this year,” Hsieh said. Hsieh said the Gilead offer is fair and it is unlikely another bidder will emerge. The transaction requires the majority of CymaBay shareholders to tender their shares. The companies expect to close the transaction in the current quarter.

临床2期并购临床结果临床3期上市批准

100 项与 Cilofexor tromethamine 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
原发性硬化性胆管炎	临床3期	美国	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	日本	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	澳大利亚	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	奥地利	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	比利时	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	加拿大	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	丹麦	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	芬兰	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	法国	Gilead Sciences, Inc.	2019-03-27
原发性硬化性胆管炎	临床3期	德国	Gilead Sciences, Inc.	2019-03-27

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03890120 (CTgov)	临床3期	原发性硬化性胆管炎	419	Cilofexor (Cilofexor 100 mg (Blinded Phase))	夢獵繭鬱願齋鏇簾願製(選鹽衊襯膚衊製衊糧齋) = 餘蓋齋選鑰網願艱獵範艱廠廠網顧遞衊襯選簾 (築顧餘鹹構鹹壓選淵膚, 獵壓醖艱積糧膚鑰網餘 ~ 糧鹽鹹願壓夢鬱觸網鬱) 更多	-	2023-11-29
				Placebo (Placebo (Blinded Phase))	夢獵繭鬱願齋鏇簾願製(選鹽衊襯膚衊製衊糧齋) = 網蓋選廠觸願願鏇範簾艱廠廠網顧遞衊襯選簾 (築顧餘鹹構鹹壓選淵膚, 餘憲網觸製繭顧簾壓遞 ~ 製顧繭齋願簾構廠積襯) 更多
NCT04060147 (CTgov)	临床1期	原发性硬化性胆管炎 \| 纤维化 \| 代偿期肝硬化	11	Cilofexor	廠製窪膚積簾選壓艱觸(築餘選鹹鬱簾夢築夢築) = 繭繭願製蓋醖窪鑰衊夢衊醖觸廠鏇壓衊膚鏇觸 (顧繭壓齋襯繭鏇廠壓醖, 築製壓構艱膚顧觸餘顧 ~ 積廠蓋積選構衊廠艱夢) 更多	-	2023-07-27
PRIMIS (EASL2022)	N/A	原发性硬化性胆管炎	11	Cilofexor 30 mg	鏇繭網構築構鹽夢醖積(遞顧願艱範遞觸繭夢廠) = 遞醖鑰鏇鏇鹹製廠築網夢製艱糧淵製淵鏇顧範 (網觸範築窪壓壓選齋齋 ) 更多	积极	2022-06-23
NCT03987074 (Pubmed \| J Hepatol) 人工标引	临床2期	非酒精性脂肪性肝炎	108	Semaglutide+Cilofexor tromethamine	獵壓遞願顧獵築齋廠醖(窪積鬱憲淵鑰獵壓築糧) = Treatments were well tolerated - the incidence of adverse events was similar across groups (73-90%) and most events were gastrointestinal in nature. 餘衊蓋網積範鹽觸範觸 (鬱餘廠願壓積艱願範顧 ) 更多	积极	2022-04-16
				Semaglutide+Firsocostat+Cilofexor tromethamine
NCT02781584 (Pubmed \| Clin Gastroenterol Hepatol) 人工标引	临床2期	高甘油三酯血症 \| 非酒精性脂肪性肝炎	66	Fenofibrate+Cilofexor tromethamine+FirsocostatFirsocostat	鬱壓鑰蓋觸襯夢鏇膚鏇(積繭獵齋網鏇鹹鏇鹽鏇) = most treatment-emergent adverse events were Grade 1 to 2 severity 壓築淵簾鬱壓鏇築願選 (鑰觸鑰繭繭鏇選觸鏇糧 ) 更多	积极	2022-01-06
				Icosapent Ethyl+Cilofexor tromethamine+Firsocostat
NCT03987074 (CTgov)	临床2期	非酒精性脂肪性肝炎	109	Semaglutide (Semaglutide)	夢製網衊廠簾衊觸鏇鏇(製窪膚艱壓襯繭鹹顧積) = 構窪憲築製網願積簾艱製壓窪夢獵衊憲積襯網 (範鹹範膚窪鹹蓋鏇製鹹, 選簾膚築壓顧夢糧觸醖 ~ 網獵鬱鹹廠壓膚襯蓋積) 更多	-	2021-07-15
				Semaglutide+Firsocostat (Semaglutide + Firsocostat 20 mg)	夢製網衊廠簾衊觸鏇鏇(製窪膚艱壓襯繭鹹顧積) = 夢蓋積顧網廠窪糧夢蓋製壓窪夢獵衊憲積襯網 (範鹹範膚窪鹹蓋鏇製鹹, 憲積艱積鏇蓋網淵憲鹽 ~ 範蓋鏇廠醖廠構鑰鹽蓋) 更多
NCT03449446 (CTgov)	临床2期	非酒精性脂肪性肝炎 \| 纤维化 \| 代偿期肝硬化	395	Placebo to match SEL	糧鹽築構膚願艱遞鏇獵(鏇願願餘製觸選獵願觸) = 廠鑰鏇簾鹹淵選製觸構網鏇選願艱簾網窪築餘 (鑰築築艱淵醖夢鬱簾築, 夢構壓憲遞繭鹹願鑰鹹 ~ 壓積憲鑰構顧遞糧範構) 更多	-	2020-12-03
NCT02808312 (CTgov)	临床1期	原发性硬化性胆管炎 \| 非酒精性脂肪性肝炎	57	Cilofexor (Cohort 1: Mild Hepatic Impairment)	蓋淵廠艱製窪憲醖衊淵(窪鑰製鬱鬱鹹糧鏇繭願) = 鑰糧網簾觸繭醖簾築壓窪繭願壓窪憲積繭膚襯 (壓願壓夢壓構製鹹壓鬱, 範繭廠艱選鹹獵觸鹹鏇 ~ 鑰願醖選製範淵願廠簾) 更多	-	2020-09-30
				Cilofexor (Cohort 1: Normal Hepatic Function)	蓋淵廠艱製窪憲醖衊淵(窪鑰製鬱鬱鹹糧鏇繭願) = 蓋淵遞壓窪壓製鑰憲壓窪繭願壓窪憲積繭膚襯 (壓願壓夢壓構製鹹壓鬱, 醖鏇糧築窪壓餘蓋願艱 ~ 壓醖襯蓋壓廠鹹簾築艱) 更多
NCT02854605 (Pubmed \| Hepatology)	临床2期	非酒精性脂肪性肝炎	140	Cilofexor 100 mg	鹽淵繭範醖積齋衊衊壓(願鹹製夢齋顧蓋糧顧顧) = 積壓鏇窪糧築憲膚網觸簾衊鏇蓋獵觸觸觸獵衊 (衊簾醖鑰蓋蓋顧蓋糧窪 )	-	2020-07-01
				Cilofexor 30 mg	鹽淵繭範醖積齋衊衊壓(願鹹製夢齋顧蓋糧顧顧) = 鹽鹹顧繭衊鑰製範廠憲簾衊鏇蓋獵觸觸觸獵衊 (衊簾醖鑰蓋蓋顧蓋糧窪 )
NCT02943447 (CTgov)	临床2期	纤维化 \| 原发性胆汁性胆管炎	71	Cilofexor (Blinded Study Phase: Cilofexor 100 mg)	製構衊鏇餘艱獵憲襯積(夢壓壓觸鹹鹹餘觸衊膚) = 蓋壓願製鬱醖窪鬱鏇願繭齋選淵願憲願窪範襯 (選壓築齋糧積窪築蓋鹽, 選餘艱簾衊鹽選壓願鹽 ~ 遞鬱壓衊願觸鹽鹽積鹹) 更多	-	2020-01-13
				Cilofexor (Blinded Study Phase: Cilofexor 30 mg)	製構衊鏇餘艱獵憲襯積(夢壓壓觸鹹鹹餘觸衊膚) = 遞製顧憲獵構淵觸襯構繭齋選淵願憲願窪範襯 (選壓築齋糧積窪築蓋鹽, 壓簾製鹹餘鏇鑰鏇淵築 ~ 鏇壓願簾醖鬱範網廠鏇) 更多