CYP7A1

Vivet Therapeutics Presents Three Posters on Cerebrotendinous Xanthomatosis Program and Novel AAV Gene Delivery Platform at European Society of Gene and Cell Therapy Annual Congress 2024 Paris, France, October 22, 2024 – Vivet Therapeutics (“Vivet”), a clinical stage biotech company developing novel and long-lasting gene therapies for rare inherited liver metabolic disorders, today announces the presentation of three posters demonstrating key pre-clinical findings for its gene therapy program, VTX-806 for the treatment of Cerebrotendinous Xanthomatosis (CTX), a study on S/MAR-containing AAV vector integration in hereditary tyrosinemia type I (HT1) and validation of the translational value of the B6.129-Cyp27a1tmlEl t/J CTX mouse model at the European Society for Gene and Cell Therapy (ESGCT) 2024 Congress Rome, Italy from the 22-25 October. Dr Gloria Gonzalez-Aseguinolaza, Co-Founder & Chief Scientific Officer at Vivet Therapeutics, said, “Our findings highlight the potential of our diversified gene therapy pipeline, using our precise, highly engineered, next-generation viral vectors and gene constructs. We are committed to developing long-lasting AAV-based gene therapies for CTX and other rare inherited liver metabolic disorders to ultimately provide more effective treatment options for patients. Dr Jean-Philippe Combal, Co-Founder & Chief Executive Officer at Vivet Therapeutics added, “The existing standard of care (SOC) for CTX is a lifelong treatment using chenodeoxycholic acid which reduces the levels of toxic metabolites but does not 100% prevent neurodegeneration, leaving an unmet medical need. Our preclinical findings for VTX-806 provide further evidence that VTX-806 holds promise for curative treatment for CTX as underlined by our data and the European Orphan Drug Designation received in September of this year. We look forward to presenting further groundbreaking data at upcoming scientific conferences as we drive the program forward.” Poster one entitled “Long-term metabolic, phenotypic, and neuropathological characterization of the Cyp27a1-/- mouse model of cerebrotendinous xanthomatosis,” details the long-term evaluation of B6.129-Cyp27a1tmlEl t/J, a CTX mouse model with full metabolic, phenotypic, histological and neuropathological characterization up to 18 months of age. The study confirmed prior literature in that Cyp27a1-/- mice when compared to their wild-type (WT) littermates, had hepatomegaly, increased levels of plasma ALT, and increased expression of Cyp7a1 and Cyp3a11. Cyp3a11 is a homolog to human CYP3A4, an enzyme that metabolizes large portions of drugs and other foreign objects in the body. At six months of age, Cyp27a1-/- mice presented lower body weight gain and steatosis, alongside elevated toxic bile acid precursors in circulation and in the brain. In addition, Cyp27a1-/- mice presented signs of ataxia, particularly in females, making this study the first to show measurable motor alterations in a mouse model with CTX, like those described in CTX patients, making this a valuable model for translational CTX research. Poster two entitled “S/MAR-Containing AAV Vectors Result in an Increase in AAV Episomes and a Reduction in AAV Integration Sites in a Mouse Model With a High Rate of Hepatocyte Proliferation,” details an S/MAR (scaffold/matrix attachment region) containing AAV vector integration study in an HT1 mouse model (Fah1R Tyrc/RJ). Results showed that the S/MAR-containing AAVs achieved a higher therapeutic effect than the control vector. Surviving mice showed body weight (BW) and serum biomarker (SB) normalization after approximately 50 days post-injection and the number of viral genomes and disease-associated enzyme (Hfah) expression levels were similar across experimental groups. Immunohistochemistry (IHC) also showed FAH expression in clusters of positive hepatocytes in recovered mice, suggesting potential AAV integration and clonal expansion. These results not only indicate the presence of the S/MAR sequence but also suggest the location of the S/MAR sequence within the therapeutic vector, influences the fate of the viral genome in the transduced cell. Poster three entitled “Liver-directed gene therapy normalizes toxic bile acid metabolite levels in the blood and brain of mice with cerebrotendinous xanthomatosis,” details the development and optimization of VTX-806, as an adeno-associated virus (AAV) vector with high potency and low immunogenicity. AAVs were optimized using Cyp27a1 expression cassettes containing a liver-specific promoter designed to prevent potential activation of an innate immune response and added regulatory elements: minute virus of mice small intron (MVM) and Woodchuck Hepatitis Virus post-transcriptional regulatory element (WPRE). Results demonstrated in vitro and in vivo higher Cyp27a1 expression with VTX-806, restoring normal levels of circulating 7αC4, expression of hepatic bile acid synthesis-related genes, and corrected hepatomegaly. Importantly, normal levels of 7αC4 were restored in the brain. These results demonstrate for the first time that liver-directed AAV gene therapy can normalize levels of toxic metabolites in the brain, offering a potentially effective and curative treatment option for CTX patients. Details of poster presentations are as follow: Poster Title: Long-term metabolic, phenotypic, and neuropathological characterization of the Cyp27a1-/- mouse model of cerebrotendinous xanthomatosis Poster Number: P0381Presenter: Laia Trigueros Motos, Research Scientist at Vivet TherapeuticsDate and Time: Tuesday 22 October at 19:30-21:00 CESTLocation: Forum Poster Title: S/MAR-Containing AAV Vectors Result in an Increase in AAV Episomes and a Reduction in AAV Integration Sites in a Mouse Model With a High Rate of Hepatocyte Proliferation Poster Number: P0138Presenter: Andrea Llanos Ardaiz, PhD Apprentice at Vivet TherapeuticsDate and Time: Wednesday 23 October at 13:30-15:00 CESTLocation: Concourse Level – 1 and Mezzanine Concourse Poster Title: Liver-directed gene therapy normalizes toxic bile acid metabolite levels in the blood and brain of mice with cerebrotendinous xanthomatosis Poster Number: P0888Presenter: Laia Trigueros Motos, Research Scientist at Vivet TherapeuticsDate and Time: Thursday 24 October at 18:00-19:30 CESTLocation: Concourse Level – 1 and Mezzanine Concourse Poster 1 Authors: L Trigueros-Motos3,‡, A Molina1,2,‡, G Pérez1,2, I Marcilla1,2, M Molina1,2, L Neri3, D Moreno-Luqui1,2, A Douar4, JP Combal4, A García-Osta 1,2, M Cuadrado-Tejedor 1,2, B Tamarit4, C Bouquet4, G Despres5, P Krasniqi5, A Lamazière5, 6, R Hernandez-Alcoceba1, G González-Aseguinolaza1,2,3,* 1 Division of DNA and RNA Medicine, CIMA, University of Navarra, Pamplona, Spain 2 Institute for Sanitary Research (IdiSNA), Pamplona, Spain 3 Vivet Therapeutics S.L., Spain 4 Vivet Therapeutics S.A.S., Paris, France 5 Sorbonne Université, Saint Antoine Research Center, INSERM UMR 938, Paris, France 6 Département de Métabolomique Clinique, Hôpital Saint Antoine, AP-HP, Sorbonne Université, Paris, France ‡Equal contribution, *ggonzalez@vivet-therapeutics.com Poster 2 Authors: A Llanos-Ardaiz1, A Lantero1, M Ruiz de Galarreta1, L Neri1, I Mauleón 2, M Bilbao-Arribas 2,3, B Tamarit4, V Ferrer4, A Douar4, JP Combal4, R Aldabe2, G Gonzalez-Aseguinolaza 1,2 1 Vivet Therapeutics S.L., Pamplona, Spain. 2 DNA & RNA Medicine Division, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. 3 IdISNA, Navarra Institute for Health Research, Pamplona, Spain. 4 Vivet Therapeutics S.A.S., Paris, France Poster 3 Authors: A Molina1,2,‡, L Trigueros-Moto 3,‡, G Pérez1,2, M Molina1,2, I Marcilla-García1,2, L Neri3, A Douar4, JP Combal4, B Tamarit4, C Bouquet 4, P Krasniqi 5, A Lamazière5, 6, R Hernandez-Alcoceba1, G González-Aseguinolaza1,2,3,* 1 Division of DNA and RNA Medicine, CIMA, University of Navarra, Pamplona, Spain 2 Institute for Sanitary Research (IdiSNA), Pamplona, Spain 3 Vivet Therapeutics S.L., Spain 4 Vivet Therapeutics S.A.S., Paris, France 5 Sorbonne Université, Saint Antoine Research Center, INSERM UMR 938, Paris, France 6 Département de Métabolomique Clinique, Hôpital Saint Antoine, AP-HP, Sorbonne Université, Paris, France ‡Equal contribution, *ggonzalez@vivet-therapeutics.com -Ends- For further information, please contact: Optimum Strategic Communications Mary Clark, Zoe Bolt, Vareen OuthonesackTel: +44 (0) 20 3882 9621Email: vivet@optimumcomms.com About Vivet Therapeutics Vivet Therapeutics is a private, clinical-stage biotech company developing novel and long-lasting gene therapies for rare inherited metabolic conditions, including Wilson’s Disease. Vivet’s gene therapy platform uses recombinant adeno-associated viruses (rAAVs) as vectors and has initiated two clinical programs and four pre-clinical assets to date. Its most advanced program VTX-PID, is aimed at depleting Neutralizing Antibodies (NAbs) levels for a given AAV serotype and is advancing in a Phase 1 dose escalating study in Nabs+ subjects. Its Leading pre-clinical program VTX-806, for the treatment of Cerebrotendinous Xanthomatosis (CTX), received ODD by the EC in September 2024 and is demonstrating its potential as an alternative treatment option for patients affected by the burden of CTX. Vivet Therapeutics was founded in 2016 by CEO Dr Jean-Philippe Combal and CSO Dr Gloria Gonzalez-Aseguinolaza and is led by a highly experienced management team with deep expertise developing gene therapies and orphan drugs. Vivet Therapeutics was founded in 2016 by CEO Dr Jean-Philippe Combal and CSO Dr Gloria Gonzalez-Aseguinolaza and is led by a highly experienced management team with deep expertise developing gene therapies and orphan drugs. Vivet Therapeutics is backed by international life science investors including Novartis Venture Fund, Roche Venture Fund, HealthCap, Pfizer Inc., Columbus Venture Partners, Ysios Capital, Kurma Partners and Eurazeo. In 2019, key investor Pfizer contributed a €45M investment to collaborate with Vivet in recognition of its scientific expertise and innovative technology platforms. For more information, please visit www.vivet-therapeutics.com - Follow us on LinkedIn @Vivet Therapeutics and Twitter @Vivet_tx…………………………

关注并星标CPHI制药在线近日，CymaBay Therapeutics（以下简称"CymaBay"）宣布了其核心管线seladelpar治疗原发性胆汁性胆管炎（PBC）的全球III期ENHANCE研究结果，引发市场关注。       值得一提的是，今年2月12日，吉利德曾以每股32.5美元的价格现金收购CymaBay，总股权价值约为43亿美元。此次收购将进一步扩充吉利德肝脏领域的产品线组合。同时seladelpar也成为吉利德重返肝病领域的一把"利剑"。那么，seladelpar有哪些独特优势？       PPARδ激动剂：Seladelpar       Seladelpar是一款强效、选择性过氧化物酶体增殖物激活受体（PPAR）δ激动剂，具有调节胆汁酸合成、炎症、纤维化和脂质代谢、储存和运输基因的能力。       PPARδ属于PPARs的一种。PPARs是一类核转录因子，能够调控多种参与细胞内外脂类代谢的目的基因表达，以及脂肪细胞的分化。PPAR基因有PPARα、β、γ三种亚型，β亚型也叫PPARδ，其几乎在所有组织均有低水平表达。       在针对PBC患者的全球III期RESPONSE研究中，评估了使用seladelpar与安慰剂相比，在对熊去氧胆酸 （UDCA） 反应不足或不耐受的原发性PBC患者中的有效性和安全性。       结果显示：在seladelpar 10 mg组和5 mg组，分别有78.2%和57.1%的患者达到了复合终点，而安慰剂组仅有12.5%达到了复合终点。接受5 mg和10 mg seladelpar治疗的患者中，碱性磷酸酶（ALP）恢复正常的比例分别为5.4% (p= 0.08)和27.3% (p < 0.0001)；而接受安慰剂治疗的患者中ALP恢复正常的比例为0%。目前，ALP是受到FDA认可的治疗PBC的替代终点。       此次RESPONSE研究的公布，揭示了seladelpar在PBC治疗领域的潜力。       PBC领域新药研发进展       PBC是一种罕见的慢性进行性自免肝病，会导致肝硬化和肝功能衰竭，免疫应答失常被认为是PBC发病的重要原因。目前获FDA批准用于PBC治疗的药物仅2款：熊去氧胆酸（UDCA）和奥贝胆酸（Ocaliva），其中接受熊去氧胆酸治疗的患者中，约有40%的患者不产生治疗应答；奥贝胆酸则因肝损伤风险被FDA给予黑框警告。因此，寻找安全、有效的治疗药物无比紧迫。       目前，PBC治疗新药主要分为PPAR激动剂、FXR激动剂、IBAT抑制剂等。       PPAR激动剂       PPAR激动剂代表药物除了CymaBay的Seladelpar外，还有印度Zydus Cadila公司的Saroglitazar，这是一款PPARα/γ双重激动剂，同时具有调节PPARα和PPARγ活性的功能。Saroglitazar最早于2013年9月在印度获批，用于治疗非他汀类药物控制的2型糖尿病患者的糖尿病血脂异常和高甘油三酯血症。       在治疗对UDCA应答不佳的PBC患者的临床试验中，在Saroglitazar 4mg组和 2mg组与对照组相比，第4周时，Saroglitazar 4mg组和2mg组的ALP水平均迅速降低，这在整个治疗过程中一直持续。第16周时，Saroglitazar 4mg、2mg和对照组中，GGT（谷氨酰转移酶）水平分别降低79.7U/L、124.5U/L和30.9U/L。与基线相比，ALP水平降低≥15%患者百分比在Saroglitazar 4mg（84.6%）和2mg组（92.9%），均显著高于对照组（仅20%）。       本研究表明Saroglitazar即使在对UDCA无反应的患者中也可能起作用，为难治性PBC患者提供了新的、有潜力的治疗方法。       FXR激动剂       法尼醇X受体（FXR）是一种参与胆汁酸稳态调节的核激素受，可抑制胆酸合成限速酶基因CYP7A1的表达，抑制胆汁酸（BA）合成；其次，可以抑制肝细胞NTCP/OATP表达，抑制BA重吸收；而且可以促进肝细胞BSEP表达，从而促进BA排泄。因此，FXR被视为治疗PBC的理想靶点。       奥贝胆酸就是一款FXR激动剂，除此之外，代表药物还有Tropifexor，这是一款由诺华研发的FXR激动剂，在PBC患者治疗中，GGT和ALP均有改善，但ALP下降幅度低，存在瘙痒副作用。       IBAT抑制剂       回肠胆汁酸转运蛋白（IBAT）抑制剂主要用来开发治疗PBC患者的胆汁淤积性瘙痒症，目前已进展至全球III期临床。在PBC患者中，用于肝脏的胆汁流出受到干扰，产生的过量胆汁酸被认为会引起胆汁淤积性瘙痒，且不能通过抓挠来缓解，可使人衰弱、疲劳等，甚至需要进行肝移植。       GSK研发的linerixibat是一种IBAT小分子抑制剂，通过阻断小肠中胆汁酸的吸收，减少循环中瘙痒性胆汁酸，从而达到缓解瘙痒的目的。       在一项针对PBC胆汁淤积性瘙痒患者进行的IIb期研究中，结果显示，linerixibat可显著改善患者的瘙痒程度。       PBC作为一种慢性胆汁淤积性肝病，在我国发病率及患病率均呈逐渐上升的趋势。尽管UDCA 可以改善患者的长期预后和生存率，但仍有约40%的患者应答不佳，由于现有可用药物的局限性，研究者开始寻求新的治疗药物，其中以FXR激动剂和PPAR激动剂潜力最大。       主要参考资料：       1.Raj Vuppalanchi, Stephen H. Caldwell，Nikolaos Pyrsopoulos，et al.Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis[J].J Hepatol.2022；76:75-85.       2.https://us.gsk.com/en-us/media/press-releases/gsk-presents-phase-2b-data-on-linerixibat-for-the-treatment-of-cholestatic-pruritus-in-primary-biliary-cholangitis-pbc/.       【智药研习社近期线下课程预告】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~

综上所述，该研究阐明了猪去氧胆酸（HDCA）通过肠（肠道菌群与肠道FXR信号通路）-肝脏（CYP7B1、PPARα）轴缓解肝脏脂质堆积，改善非酒精性脂肪性肝病（NAFLD）的分子机制 上海交通大学医学院附属第六人民医院贾伟、郑晓皎、贾伟平教授团队在 Cell Metabolism 期刊发表了题为：Hyodeoxyholic acid alleviates non-alcoholic fatty liver disease through modulating the gut-liver axis 的研究论文。 该研究揭示了猪去氧胆酸通过肠肝轴治疗非酒精性脂肪性肝病（NAFLD）的新机制，也为其提供了潜在的靶点与干预手段。 研究人员对非酒精性脂肪性肝病临床队列以及饮食诱导小鼠模型的血清/肝脏样本进行胆汁酸靶向代谢组学分析，结果发现猪去氧胆酸（hyodeoxycholic acid，HDCA）随着疾病的进展逐渐降低，且与代谢性指标呈显著负相关。进一步，研究人员用HDCA干预多种非酒精性脂肪性肝病模型小鼠（饮食诱导、基因敲除），发现肝脏脂质堆积、炎症、纤维化均得到显著的缓解。 为了探究HDCA缓解肝脏脂质代谢的分子机制，利用转录组测序分析方法，研究人员发现肝脏胆汁酸替代合成途径合成酶-CYP7B1显著上调，而经典途径合成酶-CYP7A1显著下调。胆汁酸替代合成途径已被证明在调节机体代谢中发挥着至关重要的作用。进一步，对小鼠模型的肝脏CYP7B1进行干预，证明CYP7B1是HDCA发挥作用的一个关键靶点。 那么HDCA是如何影响这两个酶的表达？首先，基于前期实验结果，研究人员先发现了HDCA可以显著抑制肠道FXR信号通路。有趣的是，单纯抑制肠道FXR信号通路，并不能复现肝脏CYP7A1显著下调的结果，因此研究人员猜测可能存在其他因素在发挥作用。利用宏基因组测序分析、粪菌移植等方法，研究人员发现了一种益生菌——狄氏副拟杆菌（Parabacteroides distasonis）在HDCA干预后丰度显著增高，体外实验证明HDCA可以直接促进狄氏副拟杆菌的生长。 狄氏副拟杆菌是如何介导调控肝脏胆汁酸合成酶？基于肝脏转录学测序结果，研究人员发现PPAR信号通路在HDCA干预后显著上调，结合代谢组学检测，最终研究人员确定一种长链多不饱和脂肪酸——γ亚麻酸，在HDCA干预后显著增加。进一步，研究人员通过体外细胞实验、荧光素酶报告基因实验确定了γ亚麻酸通过激活PPARα下调CYP7A1的表达。 综上所述，该研究阐明了猪去氧胆酸（HDCA）通过肠（肠道菌群与肠道FXR信号通路）-肝脏（CYP7B1、PPARα）轴缓解肝脏脂质堆积，改善非酒精性脂肪性肝病（NAFLD）的分子机制，为代谢性疾病中多器官对话的机制性研究提供了新的理论依据，同时为非酒精性脂肪性肝病的防治提供了新的干预策略。 上海交通大学医学院附属第六人民医院贾伟教授、郑晓皎教授、贾伟平院士为改论文共同通讯作者，上海交通大学医学院博士研究生况俊良为论文第一作者。