A Phase 3, Prospective, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Chenodeoxycholic Acid (CDCA), With an Open-Label Cohort, in Newly Diagnosed Participants With Cerebrotendinous Xanthomatosis (CTX)

This study is designed to demonstrate the beneficial effect of CDCA in the treatment of CTX-associated diarrhea in approximately 10 participants aged 2-75 years old with newly diagnosed CTX or suspected CTX who have never received treatment with CDCA.

开始日期2024-05-27

申办/合作机构

Leadiant Biosciences, Inc.

NCT06180057 / Completed临床1期

Randomized, Two-way, Two-period, Single Oral Dose, Open-label, Crossover, Bioequivalence Study to Compare Chenodeoxycholic Acid Capsules (250mg Chenodeoxycholic Acid) [Dose: 1 x 02 Capsules] Versus Chenodeoxycholic Acid Leadiant 250 mg Hard Capsules (250mg Chenodeoxycholic Acid) [Dose: 1 x 02 Capsules] in Healthy Subjects Under Fasting Conditions

Randomized, two-way, two-period, single oral dose, open-label, crossover, bioequivalence study to compare Chenodeoxycholic acid capsules (250mg chenodeoxycholic acid) [dose: 1 x 02 capsules] versus Chenodeoxycholic acid leadiant 250 mg hard capsules (250mg chenodeoxycholic acid) [dose: 1 x 02 capsules] in healthy subjects under fasting conditions.

开始日期2022-06-12

申办/合作机构-

EUCTR2021-003823-14-NL / Unknown status临床4期IIT

Pharmacokinetic cross-over study of compounded chenodeoxycholic acid. - CDCA-PK

开始日期2021-11-16

申办/合作机构-

100 项与鹅去氧胆酸相关的临床结果

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100 项与鹅去氧胆酸相关的转化医学

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100 项与鹅去氧胆酸相关的专利（医药）

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项与鹅去氧胆酸相关的文献（医药）

2024-12-01·JOURNAL OF NUTRITIONAL BIOCHEMISTRY

Chenodeoxycholic acid fortified diet drives ovarian steroidogenesis to improve embryo implantation through enhancing uterine receptivity via progesterone receptor signaling pathway in rats

Article

作者: Chen, Meixia ; Zhao, Xiaoyi ; Liu, Hui ; Wang, Jing ; Zhu, Longlong ; Chang, Zhuo ; Zhang, Dongyang ; Wang, Sixin

Infertility is a worldwide reproductive health problem influenced by the embryo implantation efficiency. We previously revealed that dietary chenodeoxycholic acid (CDCA) positively influence the early embryo implantation. But how CDCA regulate embryo implantation is largely unexplored. Herein, we investigated the mechanism behind CDCA's regulation on embryo implantation in rats. Results showed that CDCA promoted uterine receptivity, leading to increased number of implantation sites. Mechanistically, CDCA reshaped maternal amino acid metabolism and enhanced serum progesterone levels. CDCA enhanced ovarian progesterone synthesis by improving steroidogenesis-related protein (StAR and CYP11A1) expression via Takeda G-protein-coupled receptor 5. Elevated progesterone exaggerated uterine progesterone but weakened the estradiol signaling in the CDCA group, contributing to better uterine receptive for embryo implantation. Additionally, elevated transcription repressor Stat5b induced the down-regulation of progesterone-metabolizing enzyme 20-hydroxysteroid dehydrogenase 20α-HSD, complementally explained uterine progesterone signaling enhancement. Overall, our data revealed that CDCA drove ovarian steroidogenesis to improve embryo implantation through enhancing uterine receptivity via progesterone receptor pathway in rats. Therefore, CDCA diet may be a potential favorable nutritional strategy for infertility and pregnancy management.

2024-12-01·SCIENCE OF THE TOTAL ENVIRONMENT

Combined effects of polyvinyl chloride or polypropylene microplastics with cadmium on the intestine of zebrafish at environmentally relevant concentrations

Article

作者: Li, Huan ; Chen, Ling ; Liu, Yuxuan ; Wu, Bing ; Yang, Zhongchao ; Sun, Peipei

Cadmium (Cd) is a common additive in polyvinyl chloride (PVC) and polypropylene (PP) plastics. Aquatic organisms were inevitably co-exposed to PVC/PP microplastics (MPs) and Cd, but their combined toxicity is still unknown. In this study, adult zebrafish were exposed to 200 μg/L MPs (PVC or PP) and 10 μg/L Cd alone or in combination for 28 days to investigate their toxicity and mechanisms. Results showed that combined exposure with PVC/PP enhanced the Cd accumulation in the zebrafish intestine. Subsequently, toxicology analyses showed that both PVC and PP possessed synergistic toxicity with Cd, manifested by the exfoliation and necrosis of intestinal epithelial cells, and increased levels of interleukin-1β (IL-1β), superoxide dismutase (SOD) and malondialdehyde (MDA). PP exhibited a stronger synergistic effect than PVC. Integration of non-targeted metabolomics and 16S rRNA gene sequencing revealed that combined exposure to PVC and Cd induced intestine toxicity mainly through bile acid (BA) biosynthesis, fructose (Fru) and mannose (Man) metabolism, and pentose phosphate pathway (PPP). The combined exposure of PP and Cd induced toxicity through the arginine (Arg) and glutathione (GSH) metabolisms. Meanwhile, combined exposure of PVC/PP and Cd increased the abundance of intestinal Proteobacteria and pathogen Vibrio, and decreased the abundance of Gemmobacter. These changes indrectly promoted the synergistic toxicity of PVC/PP and Cd through metabolites, such as indole-3-pyruvate (IPyA), chenodeoxycholic acid (CDCA), and cholic acid (CA). These findings highlighted that more attention should be paid to the toxicity of chemicals at environmentally relevant concentrations, particularly those co-existing with MPs.

2024-11-01·INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES

Cofactor-dependence alteration of 7β-hydroxysteroid dehydrogenase: Enhancing one-pot synthesis efficiency of chenodeoxycholic acid to ursodeoxycholic acid through cofactor self-recycling

Article

作者: Xie, Xiubing ; Zhang, Rongzhen ; Huang, Runyi ; Zhang, Wenchi

NAD⁺-dependent 7α-hydroxysteroid dehydrogenase (7α-HSDH) and NADPH-dependent 7β-hydroxysteroid dehydrogenase (7β-HSDH) are involved in the biosynthesis of chenodeoxycholic acid (CDCA) to ursodeoxycholic acid (UDCA). To realize the one-pot synthesis of CDCA to UDCA through NAD⁺-NADH cycling, we aimed to improve the binding ability of Hyphomicrobium sp. 7β-HSDH to NADH. The 7β-HSDH structure was modeled and some potential residues to improve NADH affinity near conserved cofactor binding regions were screened, including Ala22, Gln23, Asn24, Asp44, Leu45, and Asn46. The dominant mutant A22T/Q23E/L45A/N46E significantly enhanced the binding affinity for NADH, resulting in a 44.9-fold increase in its k_cat/K_m value. It increased enzymatic activity by 65.2-fold and catalyzed the synthesis of UDCA at a yield of 77.6 % with 5 g/L 7K-LCA and 12.5 mM NADH. Molecular dynamics simulations indicated increased interactions of mutated 7β-HSDH and the ligand NADH by their spatially reduced binding distance and reaction energy. The modified cofactor-dependence of 7β-HSDH realized efficient one-pot synthesis of CDCA to UDCA through strengthening cofactor-recycling and reducing the use of cofactor, achieving 90.1 % UDCA yield and 54.1 g/L/d spatiotemporal yield when coupled with 7α-HSDH with only 0.5 mM NAD⁺ as coenzyme. This work also supplies a universal cofactor-dependence engineering technique for homologous HSDH enzymes.

项与鹅去氧胆酸相关的新闻（医药）

2024-10-22

·GlobeNewswire-Health Care

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-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…………………………

基因疗法临床1期

2024-07-25

·Business Wire

Mirum’s LIVMARLI Now Approved for PFIC in Patients 12 Months and Older

FOSTER CITY, Calif.--( BUSINESS WIRE )--Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM) today announced that the U.S. Food and Drug Administration (FDA) has approved a label expansion for LIVMARLI® (maralixibat) oral solution for the treatment of cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC). The expanded label includes use in PFIC patients 12 months and older as well as the higher concentration formulation of LIVMARLI evaluated in the MARCH Phase 3 study. “The launch of LIVMARLI in PFIC is going well and we are thrilled that it will now be available for patients 12 months and older,” said Chris Peetz, chief executive officer at Mirum. “PFIC is generally diagnosed when children are young, and initiating treatment quickly after diagnosis will help to ensure they have fewer days suffering from pruritus associated with this rare liver disease.” About LIVMARLI® (maralixibat) oral solution LIVMARLI® (maralixibat) oral solution is an orally administered, once-daily, ileal bile acid transporter (IBAT) inhibitor approved by the U.S. Food and Drug Administration for two pediatric cholestatic liver diseases. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) in the U.S. three months of age and older and in Europe for patients two months of age and older. It is also approved in the U.S. for the treatment of cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) 12 months of age and older and in Europe for the treatment of PFIC in patients three months of age and older. For more information for U.S. residents, please visit LIVMARLI.com . LIVMARLI has received Breakthrough Therapy designation for ALGS and PFIC type 2 and orphan designation for ALGS and PFIC. To learn more about ongoing clinical trials with LIVMARLI, please visit Mirum’s clinical trials section on the company’s website. IMPORTANT SAFETY INFORMATION Limitation of Use : LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein. LIVMARLI can cause side effects, including: Liver injury . Changes in certain liver tests are common in patients with Alagille syndrome and PFIC but can worsen during treatment. These changes may be a sign of liver injury. In PFIC, this can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen), bloating in your stomach area, loss of appetite or bleeding or bruising more easily than normal. Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain. Your healthcare provider may advise you to monitor for new or worsening stomach problems including stomach pain, diarrhea, blood in your stool or vomiting. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you. A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat is common in patients with Alagille syndrome and PFIC but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment and may monitor for bone fractures and bleeding which have been reported as common side effects. US Prescribing Information EU SmPC Canadian Product Monograph About Mirum Pharmaceuticals, Inc. Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare diseases affecting children and adults. Mirum has three approved medications: LIVMARLI® (maralixibat) oral solution , CHOLBAM® (cholic acid) capsules, and CHENODAL® (chenodiol) tablets. LIVMARLI, an IBAT inhibitor, is approved for the treatment of two rare liver diseases affecting children and adults. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome in the U.S. (three months and older), in Europe (two months and older), and in other regions globally. It is also approved in the U.S. in cholestatic pruritus in PFIC patients 12 months of age and older; in Europe, it is approved for patients with PFIC three months of age and older. CHOLBAM is FDA-approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies and adjunctive treatment of peroxisomal disorders in patients who show signs or symptoms or liver disease. CHENODAL has received medical necessity recognition by the FDA to treat patients with cerebrotendinous xanthomatosis (CTX). Mirum’s late-stage pipeline includes two investigational treatments for debilitating liver diseases. Volixibat, an IBAT inhibitor, is being evaluated in two potentially registrational studies including the Phase 2 VISTAS study for primary sclerosing cholangitis (PSC) and Phase 2b VANTAGE study for primary biliary cholangitis. Lastly, chenodiol, has been evaluated in a Phase 3 clinical study, RESTORE, to treat patients with CTX, with positive topline results reported in 2023. Mirum has submitted a new drug application with the FDA for the approval of chenodiol to treat CTX in the U.S. To learn more about Mirum, visit mirumpharma.com and follow Mirum on Facebook , LinkedIn , Instagram and Twitter (X) . Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the potential benefits of LIVMARLI in PFIC patients older than 12 years of age, the commercial success of LIVMARLI in PFIC generally, and the impact of the higher concentration formula of LIVMARLI. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “will,” “could,” “would,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Mirum’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Mirum’s business in general and the other risks described in Mirum’s filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Mirum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. A further description of risks and uncertainties can be found in Mirum’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors,” as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov .

临床2期上市批准临床3期突破性疗法孤儿药

2024-07-08

·BioSpace

Mirum Pharmaceuticals’ LIVMARLI Approved in the European Union for Patients with PFIC

European Commission grants LIVMARLI marketing authorization for treatment of PFIC in patients three months and older. Approval follows positive opinion from CHMP concluding LIVMARLI’s clinical benefit over existing therapy in PFIC. LIVMARLI also received positive COMP opinion recommending maintenance of Orphan Drug Designation in PFIC. FOSTER CITY, Calif.--(BUSINESS WIRE)-- Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM) today announced that the European Commission has granted marketing authorization for LIVMARLI® (maralixibat) oral solution for the treatment of progressive familial intrahepatic cholestasis (PFIC) in patients three months of age and older. The approval follows a positive opinion by the CHMP which concluded that LIVMARLI in PFIC brings significant clinical benefit based on improved efficacy and a major contribution to patient care compared to the existing approved treatment for PFIC. Further, evaluation by COMP recommended maintenance of Orphan Drug Designation for LIVMARLI in PFIC. The approval is based on data from the Phase 3 MARCH study, the largest randomized trial conducted in PFIC, with 93 patients across a range of genetic PFIC types, including PFIC1, PFIC2, PFIC3, PFIC4, PFIC6, and unidentified mutational status. Data from MARCH showed statistically significant reduction in pruritus (p<0.0001) and serum bile acids (p<0.0001) between LIVMARLI versus placebo in the All-PFIC cohort (n=64). Significant improvements were also observed in total bilirubin and growth versus placebo. The most common treatment emergent adverse event was diarrhea, which was predominantly mild, with no severe cases, and transient. “We are thrilled that the European Commission has granted marketing authorization for LIVMARLI in PFIC, acknowledging the strength of data collected and recognizing the important treatment opportunity for patients living with this rare liver disease,” said Chris Peetz, chief executive officer at Mirum. “Our hope is that LIVMARLI helps to improve key liver parameters and brings healthier days ahead to young patients diagnosed with PFIC in Europe. We are grateful to the researchers, patients, and families who made this approval possible.” “LIVMARLI’s approval provides a treatment backed by years of clinical research and meaningful data that demonstrate a reduction in cholestatic itch and prognostic markers of improved liver health, including a reduction of serum bile acids, all important signals for positive long-term outcomes,” said Professor Richard Thompson, King’s College London. “It is encouraging to know that physicians in Europe will have a new option that has the potential to improve the liver health and quality of life for patients and their families.” “The patient community in Europe will greatly benefit from LIVMARLI’s approval, supported by years of impressive data showing improvements in the most burdensome aspects of disease,” said Emily Ventura, executive director, PFIC Network. “PFIC can be life-altering and can have a devastating impact on patients. We are encouraged to see that young patients will have a new medication and hope for a life less burdened by cholestasis.” LIVMARLI is also approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients with PFIC five years of age and older. Mirum has submitted a supplemental new drug application to introduce a higher concentration formulation of LIVMARLI, used during the MARCH study, to enable label expansion for younger patients with PFIC, and expects to receive FDA feedback this year. About LIVMARLI® (maralixibat) oral solution LIVMARLI® (maralixibat) oral solution is an orally administered, once-daily, ileal bile acid transporter (IBAT) inhibitor approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) three months of age and older and for progressive familial intrahepatic cholestasis (PFIC) five years of age and older. LIVMARLI is also the only approved IBAT inhibitor approved by the European Commission for the treatment of cholestatic pruritus in patients with ALGS two months and older, and by Health Canada for the treatment of cholestatic pruritus in ALGS. For more information for U.S. residents, please visit LIVMARLI.com. LIVMARLI has received Breakthrough Therapy designation for ALGS and PFIC type 2 and orphan designation for ALGS and PFIC. To learn more about ongoing clinical trials with LIVMARLI, please visit Mirum’s clinical trials section on the company’s website. IMPORTANT SAFETY INFORMATION Limitation of Use: LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein. LIVMARLI can cause side effects, including: Liver injury. Changes in certain liver tests are common in patients with Alagille syndrome and PFIC but can worsen during treatment. These changes may be a sign of liver injury. In PFIC, this can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen), bloating in your stomach area, loss of appetite or bleeding or bruising more easily than normal. Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain. Your healthcare provider may advise you to monitor for new or worsening stomach problems including stomach pain, diarrhea, blood in your stool or vomiting. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you. A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat is common in patients with Alagille syndrome and PFIC but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment and may monitor for bone fractures and bleeding which have been reported as common side effects. US Prescribing Information EU SmPC Canadian Product Monograph About Mirum Pharmaceuticals, Inc. Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare diseases affecting children and adults. Mirum has three approved medications: LIVMARLI® (maralixibat) oral solution, CHOLBAM® (cholic acid) capsules, and CHENODAL® (chenodiol) tablets. LIVMARLI, an IBAT inhibitor, is approved for the treatment of two rare liver diseases affecting children and adults. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome in the U.S. (three months and older), in Europe (two months and older), and in other regions globally. It is also approved in the U.S. in cholestatic pruritus in PFIC patients five years of age and older. CHOLBAM is FDA-approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies and adjunctive treatment of peroxisomal disorders in patients who show signs or symptoms or liver disease. CHENODAL has received medical necessity recognition by the FDA to treat patients with cerebrotendinous xanthomatosis (CTX). Mirum’s late-stage pipeline includes two investigational treatments for debilitating liver diseases. Volixibat, an IBAT inhibitor, is being evaluated in two potentially registrational studies including the Phase 2b VISTAS study for primary sclerosing cholangitis and Phase 2b VANTAGE study for primary biliary cholangitis. Lastly, chenodiol, has been evaluated in a Phase 3 clinical study, RESTORE, to treat patients with CTX, with positive topline results reported in 2023. Mirum has filed a new drug application with the FDA for the approval chenodiol to treat CTX in the U.S. To learn more about Mirum, visit mirumpharma.com and follow Mirum on Facebook, LinkedIn, Instagram and Twitter (X). Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, the commercial success of LIVMARLI in Europe for PFIC, pricing reimbursement for LIVMARLI in any specific country, and the real world impact of LIVMARLI in PFIC. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “will,” “could,” “would,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Mirum’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Mirum’s business in general, the impact of the COVID-19 pandemic, and the other risks described in Mirum’s filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Mirum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. A further description of risks and uncertainties can be found in Mirum’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors,” as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at .

孤儿药上市批准临床2期突破性疗法临床结果

100 项与鹅去氧胆酸相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00163	鹅去氧胆酸	A05AA01	DB06777

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
先天性胆汁酸合成障碍	欧盟	Leadiant GmbH	2017-04-10
先天性胆汁酸合成障碍	冰岛	Leadiant GmbH	2017-04-10
先天性胆汁酸合成障碍	列支敦士登	Leadiant GmbH	2017-04-10
先天性胆汁酸合成障碍	挪威	Leadiant GmbH	2017-04-10
胆结石	美国	Leadiant Biosciences, Inc.	1983-07-28
胆石症	日本	Fujimoto Pharmaceutical Corp.	1983-05-27
胆汁淤积	中国	天津康宝天然药物有限公司	-

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
脑腱黄瘤病	申请上市	美国	Mirum Pharmaceuticals, Inc.	2024-06-28
脂质沉积	临床3期	美国	Leadiant Biosciences, Inc.	2022-08-10

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临床结果

适应症

分期

评价

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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


NCT04270682 (CTgov)	临床3期	脑腱黄瘤病	19	CDCA Weight-Based Dose TID	鏇齋遞顧餘網淵獵繭壓(糧選築衊積構繭壓襯鏇) = 構築遞餘鹹觸膚齋齋範餘糧遞壓膚憲蓋鏇艱餘 (願網簾積憲憲艱遞廠網, 範餘鬱廠蓋構觸製夢衊 ~ 醖齋築襯壓廠鑰顧蓋鹹) 更多	-	2024-10-28
SSIEM2023	N/A	先天性胆汁酸合成障碍3型	-	Chenodeoxycholic acid	鏇鏇窪製顧糧蓋選襯網(築襯繭蓋衊艱築構簾積) = 壓範鏇築鑰構鹽襯築蓋積遞選構鏇壓製遞艱餘 (鬱繭積鹽夢製遞醖憲鑰 ) 更多	-	2023-08-30
EASL2022	N/A	脑腱黄瘤病 cholestanol	5	Chenodesoxycholic acid (CDCA)	鬱廠鏇築繭鑰廠膚鹹壓(膚繭簾艱鑰鏇製鹹齋襯) = 鑰繭選憲願醖壓繭襯壓築鏇憲膚製築鑰鏇鬱網 (願鏇鑰築製獵鑰壓廠襯 ) 更多	积极	2022-06-24
NCT03168555 (BACH, CTgov)	临床4期	胆石症 \| 胆汁酸吸收不良（BAM）	23	chenodeoxycholic acid	鹽醖選鬱觸顧壓鹹蓋夢(獵襯遞構廠廠艱簾鹹觸) = 窪簾窪鑰衊鑰襯醖積製壓鹹觸齋膚鹽膚網膚選 (窪壓觸遞積衊繭遞獵膚, 艱餘鬱選顧製襯網觸襯 ~ 獵獵顧壓觸築衊願齋範)	-	2022-05-19
EASD2018	N/A	-	-	Atorvastatin	顧選願齋膚顧選構觸顧(襯鏇艱淵衊繭壓積鏇壓) = 簾醖選衊簾遞壓簾鏇蓋憲鏇網顧廠窪選夢窪淵 (醖襯襯繭淵構願築網醖 ) 更多	不佳	2018-10-04
EASD2018	N/A	-	-	Pravastatin	顧選願齋膚顧選構觸顧(襯鏇艱淵衊繭壓積鏇壓) = 衊積遞願窪製簾製簾觸憲鏇網顧廠窪選夢窪淵 (醖襯襯繭淵構願築網醖 ) 更多	不佳	2018-10-04
ECCO2016	N/A	胆汁酸吸收不良（BAM） FGF19 \| C4 \| bile acid species	-	chenodeoxycholic acid (Patients with idiopathic BAD)	簾蓋網顧觸範衊餘艱窪(範餘願遞顧醖網鏇膚鏇) = 範獵夢鏇膚範鏇窪蓋憲醖製廠鏇鏇壓糧壓齋糧 (願遞醖窪鹽餘糧簾觸選 )	积极	2016-02-12
ECCO2016	N/A	胆汁酸吸收不良（BAM） FGF19 \| C4 \| bile acid species	-	chenodeoxycholic acid (Healthy volunteers)	簾蓋網顧觸範衊餘艱窪(範餘願遞顧醖網鏇膚鏇) = 膚憲鹹願鹽鑰醖鹽鏇廠醖製廠鏇鏇壓糧壓齋糧 (願遞醖窪鹽餘糧簾觸選 )	积极	2016-02-12