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

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-Cyp27a1^{tmlEl 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: P0381
Presenter: Laia Trigueros Motos, Research Scientist at Vivet Therapeutics

Date and Time: Tuesday 22 October at 19:30-21:00 CEST

Location: 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: P0138
Presenter: Andrea Llanos Ardaiz, PhD Apprentice at Vivet Therapeutics

Date and Time: Wednesday 23 October at 13:30-15:00 CEST

Location: 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: P0888
Presenter: Laia Trigueros Motos, Research Scientist at Vivet Therapeutics

Date and Time: Thursday 24 October at 18:00-19:30 CEST

Location: Concourse Level – 1 and Mezzanine Concourse

Poster 1 Authors: L Trigueros-Motos^3,‡, A Molina^1,2,‡, G Pérez^1,2, I Marcilla^1,2, M Molina^1,2, L Neri³, D Moreno-Luqui^1,2, A Douar⁴, JP Combal⁴, A García-Osta ^1,2, M Cuadrado-Tejedor ^1,2, B Tamarit⁴, C Bouquet⁴, G Despres⁵, P Krasniqi⁵, A Lamazière^{5, 6}, R Hernandez-Alcoceba¹, G González-Aseguinolaza^1,2,3,*

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 Molina^1,2,‡, L Trigueros-Moto ^3,‡, G Pérez^1,2, M Molina^1,2, I Marcilla-García^1,2, L Neri³, A Douar⁴, JP Combal⁴, B Tamarit⁴, C Bouquet ⁴, P Krasniqi ⁵, A Lamazière^{5, 6}, R Hernandez-Alcoceba¹, G González-Aseguinolaza^1,2,3,*

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