Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial
Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to obse...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-12-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/24/15924 |
| _version_ | 1797406855752843264 |
|---|---|
| author | Felicitas Stoll Andrea Seidel-Glätzer Ina Burghaus Oliver Göring Max Sauter Peter Rose Volker Daniel Mathias Haag Matthias Schwab Johannes Riffel Florian André Lenka Taylor Johanna Weiss Jürgen Burhenne Volker Cleeves Walter E. Haefeli Antje Blank |
| author_facet | Felicitas Stoll Andrea Seidel-Glätzer Ina Burghaus Oliver Göring Max Sauter Peter Rose Volker Daniel Mathias Haag Matthias Schwab Johannes Riffel Florian André Lenka Taylor Johanna Weiss Jürgen Burhenne Volker Cleeves Walter E. Haefeli Antje Blank |
| author_sort | Felicitas Stoll |
| collection | DOAJ |
| description | Bile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma LDL cholesterol. In this exploratory phase I clinical trial, volunteers with LDL cholesterol > 130 mg/dL but without overt atherosclerotic disease were included. Thirteen participants received bulevirtide 5 mg/d subcutaneously for 12 weeks. The primary aim was to estimate the change in LDL cholesterol after 12 weeks. Secondary endpoints included changes in total cholesterol, HDL cholesterol, lipoprotein(a), inflammatory biomarkers, and glucose after 12 weeks. In addition, cardiac magnetic resonance imaging (CMR) was performed at four time points. BA were measured as biomarkers of the inhibition of hepatocellular uptake. After 12 weeks, LDL cholesterol decreased not statistically significantly by 19.6 mg/dL [−41.8; 2.85] (Hodges–Lehmann estimator with 95% confidence interval). HDL cholesterol showed a significant increase by 5.5 mg/dL [1.00; 10.50]. Lipoprotein(a) decreased by 1.87 mg/dL [−7.65; 0]. Inflammatory biomarkers, glucose, and cardiac function were unchanged. Pre-dose total BA increased nearly five-fold (from 2026 nmol/L ± 2158 (mean ± SD) at baseline to 9922 nmol/L ± 7357 after 12 weeks of treatment). Bulevirtide was generally well tolerated, with most adverse events being administration site reactions. The exploratory nature of the trial with a limited number of participants allows the estimation of potential effects, which are crucial for future pharmacological research on bile acid metabolism in humans. |
| first_indexed | 2024-03-09T03:32:40Z |
| format | Article |
| id | doaj.art-a4b82880def64240ac7881407185166c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T03:32:40Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a4b82880def64240ac7881407185166c2023-12-03T14:53:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123241592410.3390/ijms232415924Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical TrialFelicitas Stoll0Andrea Seidel-Glätzer1Ina Burghaus2Oliver Göring3Max Sauter4Peter Rose5Volker Daniel6Mathias Haag7Matthias Schwab8Johannes Riffel9Florian André10Lenka Taylor11Johanna Weiss12Jürgen Burhenne13Volker Cleeves14Walter E. Haefeli15Antje Blank16Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, GermanyCoordination Centre for Clinical Trials (KKS) Heidelberg, 69120 Heidelberg, GermanyCoordination Centre for Clinical Trials (KKS) Heidelberg, 69120 Heidelberg, GermanyCoordination Centre for Clinical Trials (KKS) Heidelberg, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, GermanyInstitute of Immunology, Heidelberg University Hospital, 69120 Heidelberg, GermanyDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, GermanyDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 70376 Stuttgart, GermanyDepartment of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Cardiology, Angiology and Pneumology, Heidelberg University Hospital, 69120 Heidelberg, GermanyPharmacy, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, GermanyTechnology Transfer Heidelberg GmbH, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, GermanyDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, 69120 Heidelberg, GermanyBile acids (BA) play an important role in cholesterol metabolism and possess further beneficial metabolic effects as signalling molecules. Blocking the hepatocellular uptake of BA via sodium-taurocholate co-transporting polypeptide (NTCP) with the first-in-class drug bulevirtide, we expected to observe a decrease in plasma LDL cholesterol. In this exploratory phase I clinical trial, volunteers with LDL cholesterol > 130 mg/dL but without overt atherosclerotic disease were included. Thirteen participants received bulevirtide 5 mg/d subcutaneously for 12 weeks. The primary aim was to estimate the change in LDL cholesterol after 12 weeks. Secondary endpoints included changes in total cholesterol, HDL cholesterol, lipoprotein(a), inflammatory biomarkers, and glucose after 12 weeks. In addition, cardiac magnetic resonance imaging (CMR) was performed at four time points. BA were measured as biomarkers of the inhibition of hepatocellular uptake. After 12 weeks, LDL cholesterol decreased not statistically significantly by 19.6 mg/dL [−41.8; 2.85] (Hodges–Lehmann estimator with 95% confidence interval). HDL cholesterol showed a significant increase by 5.5 mg/dL [1.00; 10.50]. Lipoprotein(a) decreased by 1.87 mg/dL [−7.65; 0]. Inflammatory biomarkers, glucose, and cardiac function were unchanged. Pre-dose total BA increased nearly five-fold (from 2026 nmol/L ± 2158 (mean ± SD) at baseline to 9922 nmol/L ± 7357 after 12 weeks of treatment). Bulevirtide was generally well tolerated, with most adverse events being administration site reactions. The exploratory nature of the trial with a limited number of participants allows the estimation of potential effects, which are crucial for future pharmacological research on bile acid metabolism in humans.https://www.mdpi.com/1422-0067/23/24/15924LDL cholesterolbulevirtidebile acidNTCPphase I clinical trial |
| spellingShingle | Felicitas Stoll Andrea Seidel-Glätzer Ina Burghaus Oliver Göring Max Sauter Peter Rose Volker Daniel Mathias Haag Matthias Schwab Johannes Riffel Florian André Lenka Taylor Johanna Weiss Jürgen Burhenne Volker Cleeves Walter E. Haefeli Antje Blank Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial International Journal of Molecular Sciences LDL cholesterol bulevirtide bile acid NTCP phase I clinical trial |
| title | Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial |
| title_full | Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial |
| title_fullStr | Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial |
| title_full_unstemmed | Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial |
| title_short | Metabolic Effect of Blocking Sodium-Taurocholate Co-Transporting Polypeptide in Hypercholesterolemic Humans with a Twelve-Week Course of Bulevirtide—An Exploratory Phase I Clinical Trial |
| title_sort | metabolic effect of blocking sodium taurocholate co transporting polypeptide in hypercholesterolemic humans with a twelve week course of bulevirtide an exploratory phase i clinical trial |
| topic | LDL cholesterol bulevirtide bile acid NTCP phase I clinical trial |
| url | https://www.mdpi.com/1422-0067/23/24/15924 |
| work_keys_str_mv | AT felicitasstoll metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT andreaseidelglatzer metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT inaburghaus metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT olivergoring metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT maxsauter metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT peterrose metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT volkerdaniel metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT mathiashaag metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT matthiasschwab metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT johannesriffel metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT florianandre metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT lenkataylor metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT johannaweiss metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT jurgenburhenne metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT volkercleeves metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT walterehaefeli metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial AT antjeblank metaboliceffectofblockingsodiumtaurocholatecotransportingpolypeptideinhypercholesterolemichumanswithatwelveweekcourseofbulevirtideanexploratoryphaseiclinicaltrial |