Andrea DeBarber PhD, Yaz Kisanuki MD, Paulo Nobrega MD, Ryan Himes MD, Suman Jayadev MD, John Bernat MD, Vikram Prakash MD, James Gibson MD, Austin Larson MD, Paulo Sgobbi PhD, Edward Murphy MS, Brian Fedor BS, Cheryl Wong Po Foo PhD, Rana Dutta PhD, Michael Imperiale MD, Will Garner PhD, Pamela Vig PhD, Sarah Perez MD, Ritesh Ramdhani MD, Jonas Saute MD, P. Barton Duell MD
{"title":"陈去氧胆酸治疗脑黄疽成人患者的评估:一项随机、安慰剂对照的3期研究","authors":"Andrea DeBarber PhD, Yaz Kisanuki MD, Paulo Nobrega MD, Ryan Himes MD, Suman Jayadev MD, John Bernat MD, Vikram Prakash MD, James Gibson MD, Austin Larson MD, Paulo Sgobbi PhD, Edward Murphy MS, Brian Fedor BS, Cheryl Wong Po Foo PhD, Rana Dutta PhD, Michael Imperiale MD, Will Garner PhD, Pamela Vig PhD, Sarah Perez MD, Ritesh Ramdhani MD, Jonas Saute MD, P. Barton Duell MD","doi":"10.1016/j.jacl.2024.04.069","DOIUrl":null,"url":null,"abstract":"<div><h3>Study Funding</h3><p>Mirum Pharmaceuticals, Inc.</p></div><div><h3>Background/Synopsis</h3><p>Cerebrotendinous xanthomatosis (CTX) is a rare metabolic disorder of bile acid synthesis caused by biallelic pathogenic variants in the CYP27A1 gene, encoding the sterol 27-hydroxylase enzyme, which leads to abnormal bile acid synthesis and toxic accumulation of cholestanol, bile alcohols and other metabolites. Chenodeoxycholic acid (CDCA) treatment is considered the standard-of-care for CTX.</p></div><div><h3>Objective/Purpose</h3><p>We evaluated the efficacy and safety of CDCA on biomarkers of CTX in the first Phase 3, randomized withdrawal, double-blind (DB), placebo (PBO)-controlled, two-period x two-treatment cross-over study with rescue medication (RESTORE).</p></div><div><h3>Methods</h3><p>A 24-week randomized withdrawal, DB, crossover study with a 30-day safety follow-up was conducted in adult patients (≥16 years of age) with CTX who received 250 mg CDCA TID for two 8-week open label (OL) periods of the study and either blinded CDCA or PBO for two 4-week DB periods. Eligible participants had a clinical diagnosis of CTX with biochemical confirmation, no known malabsorption or GI conditions, and not on cholic acid and/or medication impacting bile acid absorption. The primary endpoint was change in the urinary bile alcohol biomarker 5β-cholestane-3α,7α,12α,23S,25-pentol (23S-pentol) from Baseline (BL) to the end of each DB treatment period. Key secondary efficacy endpoints included: percent changes in plasma cholestanol and 7α-hydroxy-4-cholesten-3-one (7αC4) at end of each DB period and proportion of patients requiring rescue medication (CDCA) during the DB periods. Safety parameters were also assessed.</p></div><div><h3>Results</h3><p>The analysis included 14 participants with a median (min, max) age at enrollment of 41.5 (16, 55) years, the majority were white males, and all had a clinical diagnosis of CTX with biochemical confirmation. CDCA withdrawal after the OL treatment period resulted in a statistically significant 20-fold increase (95% CI: 10.3, 43.5 p<0.0001) in urine 23S-pentol (ng/mL), a 2.8-fold increase (95% CI: 1.5, 5.2; p=0.0083) in plasma cholestanol (µg/mL), and a 50-fold increase (95% CI: 25.0, 66.7; p<0.0001) in plasma 7αC4 (ng/mL; placebo relative to CDCA). A significant proportion of participants on PBO (61.5% [95% CI: 31.6, 86.1]; p=0.0006) required blinded rescue medication during the DB withdrawal periods. Most commonly reported TEAEs on CDCA were diarrhea (n=5) and headache (n=3) with the majority mild to moderate in severity and not considered treatment related.</p></div><div><h3>Conclusions</h3><p>Withdrawal of CDCA treatment led to significant increases in CTX biomarkers. CDCA treatment is well-tolerated and can effectively suppress abnormal bile acid synthesis in CTX, preventing accumulation of cholestanol and bile alcohols. This underscores the potential for CDCA to help CTX patients avoid disease progression.</p></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"18 4","pages":"Pages e540-e541"},"PeriodicalIF":3.6000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"†Evaluation of Chenodeoxycholic Acid Treatment in Adult Patients with Cerebrotendinous Xanthomatosis: A Randomized, Placebo-Controlled Phase 3 Study\",\"authors\":\"Andrea DeBarber PhD, Yaz Kisanuki MD, Paulo Nobrega MD, Ryan Himes MD, Suman Jayadev MD, John Bernat MD, Vikram Prakash MD, James Gibson MD, Austin Larson MD, Paulo Sgobbi PhD, Edward Murphy MS, Brian Fedor BS, Cheryl Wong Po Foo PhD, Rana Dutta PhD, Michael Imperiale MD, Will Garner PhD, Pamela Vig PhD, Sarah Perez MD, Ritesh Ramdhani MD, Jonas Saute MD, P. Barton Duell MD\",\"doi\":\"10.1016/j.jacl.2024.04.069\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Study Funding</h3><p>Mirum Pharmaceuticals, Inc.</p></div><div><h3>Background/Synopsis</h3><p>Cerebrotendinous xanthomatosis (CTX) is a rare metabolic disorder of bile acid synthesis caused by biallelic pathogenic variants in the CYP27A1 gene, encoding the sterol 27-hydroxylase enzyme, which leads to abnormal bile acid synthesis and toxic accumulation of cholestanol, bile alcohols and other metabolites. Chenodeoxycholic acid (CDCA) treatment is considered the standard-of-care for CTX.</p></div><div><h3>Objective/Purpose</h3><p>We evaluated the efficacy and safety of CDCA on biomarkers of CTX in the first Phase 3, randomized withdrawal, double-blind (DB), placebo (PBO)-controlled, two-period x two-treatment cross-over study with rescue medication (RESTORE).</p></div><div><h3>Methods</h3><p>A 24-week randomized withdrawal, DB, crossover study with a 30-day safety follow-up was conducted in adult patients (≥16 years of age) with CTX who received 250 mg CDCA TID for two 8-week open label (OL) periods of the study and either blinded CDCA or PBO for two 4-week DB periods. Eligible participants had a clinical diagnosis of CTX with biochemical confirmation, no known malabsorption or GI conditions, and not on cholic acid and/or medication impacting bile acid absorption. The primary endpoint was change in the urinary bile alcohol biomarker 5β-cholestane-3α,7α,12α,23S,25-pentol (23S-pentol) from Baseline (BL) to the end of each DB treatment period. Key secondary efficacy endpoints included: percent changes in plasma cholestanol and 7α-hydroxy-4-cholesten-3-one (7αC4) at end of each DB period and proportion of patients requiring rescue medication (CDCA) during the DB periods. Safety parameters were also assessed.</p></div><div><h3>Results</h3><p>The analysis included 14 participants with a median (min, max) age at enrollment of 41.5 (16, 55) years, the majority were white males, and all had a clinical diagnosis of CTX with biochemical confirmation. CDCA withdrawal after the OL treatment period resulted in a statistically significant 20-fold increase (95% CI: 10.3, 43.5 p<0.0001) in urine 23S-pentol (ng/mL), a 2.8-fold increase (95% CI: 1.5, 5.2; p=0.0083) in plasma cholestanol (µg/mL), and a 50-fold increase (95% CI: 25.0, 66.7; p<0.0001) in plasma 7αC4 (ng/mL; placebo relative to CDCA). A significant proportion of participants on PBO (61.5% [95% CI: 31.6, 86.1]; p=0.0006) required blinded rescue medication during the DB withdrawal periods. Most commonly reported TEAEs on CDCA were diarrhea (n=5) and headache (n=3) with the majority mild to moderate in severity and not considered treatment related.</p></div><div><h3>Conclusions</h3><p>Withdrawal of CDCA treatment led to significant increases in CTX biomarkers. CDCA treatment is well-tolerated and can effectively suppress abnormal bile acid synthesis in CTX, preventing accumulation of cholestanol and bile alcohols. This underscores the potential for CDCA to help CTX patients avoid disease progression.</p></div>\",\"PeriodicalId\":15392,\"journal\":{\"name\":\"Journal of clinical lipidology\",\"volume\":\"18 4\",\"pages\":\"Pages e540-e541\"},\"PeriodicalIF\":3.6000,\"publicationDate\":\"2024-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of clinical lipidology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1933287424001168\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of clinical lipidology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1933287424001168","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
†Evaluation of Chenodeoxycholic Acid Treatment in Adult Patients with Cerebrotendinous Xanthomatosis: A Randomized, Placebo-Controlled Phase 3 Study
Study Funding
Mirum Pharmaceuticals, Inc.
Background/Synopsis
Cerebrotendinous xanthomatosis (CTX) is a rare metabolic disorder of bile acid synthesis caused by biallelic pathogenic variants in the CYP27A1 gene, encoding the sterol 27-hydroxylase enzyme, which leads to abnormal bile acid synthesis and toxic accumulation of cholestanol, bile alcohols and other metabolites. Chenodeoxycholic acid (CDCA) treatment is considered the standard-of-care for CTX.
Objective/Purpose
We evaluated the efficacy and safety of CDCA on biomarkers of CTX in the first Phase 3, randomized withdrawal, double-blind (DB), placebo (PBO)-controlled, two-period x two-treatment cross-over study with rescue medication (RESTORE).
Methods
A 24-week randomized withdrawal, DB, crossover study with a 30-day safety follow-up was conducted in adult patients (≥16 years of age) with CTX who received 250 mg CDCA TID for two 8-week open label (OL) periods of the study and either blinded CDCA or PBO for two 4-week DB periods. Eligible participants had a clinical diagnosis of CTX with biochemical confirmation, no known malabsorption or GI conditions, and not on cholic acid and/or medication impacting bile acid absorption. The primary endpoint was change in the urinary bile alcohol biomarker 5β-cholestane-3α,7α,12α,23S,25-pentol (23S-pentol) from Baseline (BL) to the end of each DB treatment period. Key secondary efficacy endpoints included: percent changes in plasma cholestanol and 7α-hydroxy-4-cholesten-3-one (7αC4) at end of each DB period and proportion of patients requiring rescue medication (CDCA) during the DB periods. Safety parameters were also assessed.
Results
The analysis included 14 participants with a median (min, max) age at enrollment of 41.5 (16, 55) years, the majority were white males, and all had a clinical diagnosis of CTX with biochemical confirmation. CDCA withdrawal after the OL treatment period resulted in a statistically significant 20-fold increase (95% CI: 10.3, 43.5 p<0.0001) in urine 23S-pentol (ng/mL), a 2.8-fold increase (95% CI: 1.5, 5.2; p=0.0083) in plasma cholestanol (µg/mL), and a 50-fold increase (95% CI: 25.0, 66.7; p<0.0001) in plasma 7αC4 (ng/mL; placebo relative to CDCA). A significant proportion of participants on PBO (61.5% [95% CI: 31.6, 86.1]; p=0.0006) required blinded rescue medication during the DB withdrawal periods. Most commonly reported TEAEs on CDCA were diarrhea (n=5) and headache (n=3) with the majority mild to moderate in severity and not considered treatment related.
Conclusions
Withdrawal of CDCA treatment led to significant increases in CTX biomarkers. CDCA treatment is well-tolerated and can effectively suppress abnormal bile acid synthesis in CTX, preventing accumulation of cholestanol and bile alcohols. This underscores the potential for CDCA to help CTX patients avoid disease progression.
期刊介绍:
Because the scope of clinical lipidology is broad, the topics addressed by the Journal are equally diverse. Typical articles explore lipidology as it is practiced in the treatment setting, recent developments in pharmacological research, reports of treatment and trials, case studies, the impact of lifestyle modification, and similar academic material of interest to the practitioner. While preference is given to material of immediate practical concern, the science that underpins lipidology is forwarded by expert contributors so that evidence-based approaches to reducing cardiovascular and coronary heart disease can be made immediately available to our readers. Sections of the Journal will address pioneering studies and the clinicians who conduct them, case studies, ethical standards and conduct, professional guidance such as ATP and NCEP, editorial commentary, letters from readers, National Lipid Association (NLA) news and upcoming event information, as well as abstracts from the NLA annual scientific sessions and the scientific forums held by its chapters, when appropriate.