CYP27A1

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…………………………

Pre-clinical data of VTX-806 in mice demonstrated normalization of metabolic parameters in blood and brain, and of upregulated compensatory enzymes EUR 4.9 million funding provided by French Government to develop VTX-806 as an effective treatment option to stabilize or reverse symptoms in CTX patients PARIS, Sept. 5, 2024 /PRNewswire/ -- Vivet Therapeutics ("Vivet"), a clinical stage biotech company developing novel and long-lasting gene therapies for rare inherited liver metabolic disorders, today announces that the European Commission has granted Orphan Drug Designation (ODD) to VTX-806, its gene therapy product for the treatment of CTX, a rare neurodegenerative disease. Pre-clinical in vivo studies of VTX-806, an Adeno-associated viral (AAV) vector encoding human CYP27A1 for the treatment of CTX, demonstrated a reduction of hepatomegaly in mice, normalization of upregulated compensatory enzymes and of primary and secondary bile acids when compared to current standard of care (SOC) treatments. The submitted data, alongside the chronically debilitating effects of CTX associated leukodystrophies, supported the decision by the EU Commission to grant ODD to VTX-806 as a potential treatment option, bringing significant benefits to patients affected by the burden of CTX in the European Union. Dr Jean-Philippe Combal, Co-Founder & Chief Executive Officer at Vivet Therapeutics, said: "Early diagnosis and treatment of CTX is crucial to halting disease progression. At present, existing standard of care treatments can only slow or stabilize leukodystrophy, with no cure available. Preclinical data supports VTX-806's potential as an alternative treatment option to stop, or reverse, disease progression over the long-term, or possibly even cure CTX patients. Receiving ODD from the EU Commission provides Vivet with certain benefits during development and commercialization activities as we press forward with the anticipation of submitting ODD to the US FDA in 2024 and plan to begin preparations to enter clinical development in late 2025." VTX-806's ODD adoption follows the EUR 4.9 million funding Vivet received from the French government to advance the development of the gene therapy for treatment of CTX. The funding covers preclinical research and development activities of VTX-806, including manufacturing process development and a clinical study aimed at identifying neurological biomarkers for the effectiveness of treatment in patients under SOC. CTX is a rare genetic disorder caused by mutations in the CYP27A1 gene that affects the body's ability to metabolize cholesterol and bile acids. It is characterized by a buildup of cholestanol in the blood and tissues, which can accumulate in the brain, tendons, eyes, and arteries. This buildup can lead to fatty yellow nodules called xanthomas in the brain's connective tissues, which can damage the brain and other areas of the body. CTX can present at any age, resulting in chronic diarrhea during infancy, cataracts in late childhood and frequent bone fractures due to brittle bones in children. As a patient enters adulthood, they suffer with progressive leukodystrophy manifesting into dementia, seizures, hallucinations, depression and difficulty with coordination and speech. At present, there is no cure for CTX, only treatment that may stabilize or slow down disease progression. There are only several hundred identified cases of patients with CTX worldwide1, due to underdiagnosis, variability of disease presentation (including incomplete penetrance with asymptomatic carriers) and incorrect prediction of pathogenic variants by genetic epidemiology study. Therefore, the exact figure is unknown2 but it is estimated that 1000 to 2000 people are affected by CTX in the European Union3 and incidence of 0.1 per million individuals worldwide4. These estimates suggest that the actual number of patients with CTX globally is higher than currently reported. Citations: 1National Library of Medicines / A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns 2National Library of Medicines / Cerebrotendinous Xanthomatosis 3Orphanet Journal of Rare Diseases 18(1):13 / Pramparo T., et al. (2023) 'Allelic prevalence and geographic distribution of cerebrotendinous xanthomatosis.' 4Hunter's Hope / What is CTX or Cerebrotendinous Xanthomatosis? 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 therapy is VTX-801, a novel gene therapy for Wilson's Disease, with key clinical read-outs expected by the end of 2024. 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 - Follow us on LinkedIn @Vivet Therapeutics and Twitter @Vivet_tx. SOURCE Vivet Therapeutics

*仅供医学专业人士阅读参考 衰老是否可以被“治疗”？ 早在1961年，就有学者发现了细胞衰老的现象。衰老细胞会进入一种不可逆的停滞状态，并表现出分泌促炎细胞因子、蛋白酶等物质的衰老相关分泌表型（SASP）。衰老细胞广泛存在于体内，多项研究发现，细胞衰老与年龄相关疾病存在关联，因此针对衰老细胞的清除或许能够成为“治疗衰老”的良方。 针对衰老细胞的药物被统称为senolytics。其实senolytics诸位读者可能早已见过或者吃过，这类化合物中的一些天然成分并不属于处方药，在安全性和有效性都没有得到验证之前就已经在保健品中发光发热了。 不过抗衰效果口说无凭，还是要经过临床试验才说了算。近期，《自然·医学》杂志发表了一项senolytics疗法的2期临床试验结果，研究者们使用达沙替尼+槲皮素（D+Q）治疗绝经后女性的骨质流失，持续20周，未能观察到骨吸收和骨形成的显著改善。 但在衰老细胞负荷较高的参与者中，研究者观察到骨形成增加了34%，骨吸收减少11%。 论文题图 这项研究的参与者是60名绝经后妇女，年龄62-88岁，随机分配至D+Q组和对照组，治疗持续20周。通过外周血T细胞中p16 mRNA水平评估衰老细胞负荷。参与者维生素D摄入是充足的，D+Q组血清钙水平略低。 研究的主要终点是骨吸收标志物CTx的百分比变化，次要终点是骨形成标志物P1NP的百分比变化。 试验设计 遗憾的是，无论是CTx还是P1NP，在试验结束的第20周都未表现出显著的统计学差异。进一步分析桡骨、股骨颈或腰椎的密度，也没有差异。 试验第20周、第2周、第4周的骨吸收、骨形成标志物变化 虽然没效果但也没危险，参与者没有发现与D+Q有关的严重不良事件。不过有53%的参与者表示有头痛或胃肠道不适。 研究者认为衰老细胞负荷更高的参与者对D+Q更敏感，于是根据T细胞p16 mRNA水平将参与者分为三个亚组。 衰老细胞负荷最高的T3组的P1NP在第2周增加了34%，第4周增加了38%，但第20周差异消失；CTx在第2周下降11%，第4周下降了18%，第20周恢复至基线水平。相对衰老细胞负荷较低的T1/2组，可以看出明显的差异。 衰老细胞负荷影响senolytics的疗效 研究者还观察到，T3组的桡骨密度在D+Q治疗后增加了2.7%，而T1/2无差异。 由此来看，senolytics的抗衰作用其实是有条件的，到底什么人能从中受益，如何给药、多大剂量，都是需要进一步研究的问题。 研究者表示，衰老细胞在病生理中作用非常广泛，除了糖尿病、心脏病、特发性肺纤维化能涉及衰老细胞的疾病，抗癌化疗等医学过程也会增加衰老细胞的数量，senolytics或许能够为其带来正面收益。 参考资料： [1]https://www.nature.com/articles/s41591-024-03096-2 本文作者丨代丝雨