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Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome

BACKGROUND: Natural history studies are increasingly recognized as having an important role in drug development for rare diseases. A phase 3, observational, retrospective, and non-interventional study was designed to establish a natural history control (NHC) cohort of patients with Barth syndrome (B...

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Autores principales: Hornby, Brittany, Thompson, William Reid, Almuqbil, Mohammed, Manuel, Ryan, Abbruscato, Anthony, Carr, Jim, Vernon, Hilary J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438322/
https://www.ncbi.nlm.nih.gov/pubmed/36056411
http://dx.doi.org/10.1186/s13023-022-02469-5
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author Hornby, Brittany
Thompson, William Reid
Almuqbil, Mohammed
Manuel, Ryan
Abbruscato, Anthony
Carr, Jim
Vernon, Hilary J.
author_facet Hornby, Brittany
Thompson, William Reid
Almuqbil, Mohammed
Manuel, Ryan
Abbruscato, Anthony
Carr, Jim
Vernon, Hilary J.
author_sort Hornby, Brittany
collection PubMed
description BACKGROUND: Natural history studies are increasingly recognized as having an important role in drug development for rare diseases. A phase 3, observational, retrospective, and non-interventional study was designed to establish a natural history control (NHC) cohort of patients with Barth syndrome (BTHS) to provide further analysis of the efficacy of elamipretide observed in an open-label extension (OLE) phase of the TAZPOWER trial, a clinical trial that tested the efficacy of 40 mg daily of elamipretide in patients with BTHS. METHODS: This was a retrospective, non-interventional study. A propensity score model was used to compare elamipretide-treated patients and NHCs. The analysis included 8 patients from the TAZPOWER OLE and 19 untreated NHCs (including 12 with serial echocardiographic assessments). RESULTS: For the 6-min walk test (6MWT, primary endpoint), the least squares (LS) mean difference between groups was 79.7 m (P = 0.0004) at week 64 and 91.0 m (P = 0.0005) at week 76 in favor of elamipretide. Significant improvements in muscle strength (secondary endpoint), as assessed by handheld dynamometry (HHD) were also observed with elamipretide, with LS mean differences of 40.8 Newtons at 64 weeks (P = 0.0002) and 56.7 Newtons at 76 weeks (P = 0.0005). Patients continuously treated with elamipretide also experienced statistically significant improvements in other secondary endpoints (i.e., 5 times sit-to-stand [5XSST], multi-domain responder index [MDRI]). The functional improvements were robust to sensitivity analyses. Left ventricular stroke volume increased from baseline in patients with elamipretide but decreased in NHCs. CONCLUSIONS: Overall, the study established a NHC for use in assessing the efficacy of therapeutic interventions in patients with BTHS and the results suggest that elamipretide may improve natural history of BTHS at least in part by attenuating the natural decline in heart function and provide meaningful improvements in heart function and functional capacity in patients with BTHS compared to NHCs. HIGHLIGHTS: A matched Natural History Control (NHC) was used to evaluate elamipretide in BTHS. Elamipretide may improve natural history of BTHS by attenuating natural decline in heart function. Elamipretide was associated with meaningful clinical improvements in skeletal muscle and cardiovascular parameters that were not observed in NHCs. The study established a NHC for use in assessing the efficacy of therapeutic interventions in BTHS.
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spelling pubmed-94383222022-09-03 Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome Hornby, Brittany Thompson, William Reid Almuqbil, Mohammed Manuel, Ryan Abbruscato, Anthony Carr, Jim Vernon, Hilary J. Orphanet J Rare Dis Research BACKGROUND: Natural history studies are increasingly recognized as having an important role in drug development for rare diseases. A phase 3, observational, retrospective, and non-interventional study was designed to establish a natural history control (NHC) cohort of patients with Barth syndrome (BTHS) to provide further analysis of the efficacy of elamipretide observed in an open-label extension (OLE) phase of the TAZPOWER trial, a clinical trial that tested the efficacy of 40 mg daily of elamipretide in patients with BTHS. METHODS: This was a retrospective, non-interventional study. A propensity score model was used to compare elamipretide-treated patients and NHCs. The analysis included 8 patients from the TAZPOWER OLE and 19 untreated NHCs (including 12 with serial echocardiographic assessments). RESULTS: For the 6-min walk test (6MWT, primary endpoint), the least squares (LS) mean difference between groups was 79.7 m (P = 0.0004) at week 64 and 91.0 m (P = 0.0005) at week 76 in favor of elamipretide. Significant improvements in muscle strength (secondary endpoint), as assessed by handheld dynamometry (HHD) were also observed with elamipretide, with LS mean differences of 40.8 Newtons at 64 weeks (P = 0.0002) and 56.7 Newtons at 76 weeks (P = 0.0005). Patients continuously treated with elamipretide also experienced statistically significant improvements in other secondary endpoints (i.e., 5 times sit-to-stand [5XSST], multi-domain responder index [MDRI]). The functional improvements were robust to sensitivity analyses. Left ventricular stroke volume increased from baseline in patients with elamipretide but decreased in NHCs. CONCLUSIONS: Overall, the study established a NHC for use in assessing the efficacy of therapeutic interventions in patients with BTHS and the results suggest that elamipretide may improve natural history of BTHS at least in part by attenuating the natural decline in heart function and provide meaningful improvements in heart function and functional capacity in patients with BTHS compared to NHCs. HIGHLIGHTS: A matched Natural History Control (NHC) was used to evaluate elamipretide in BTHS. Elamipretide may improve natural history of BTHS by attenuating natural decline in heart function. Elamipretide was associated with meaningful clinical improvements in skeletal muscle and cardiovascular parameters that were not observed in NHCs. The study established a NHC for use in assessing the efficacy of therapeutic interventions in BTHS. BioMed Central 2022-09-02 /pmc/articles/PMC9438322/ /pubmed/36056411 http://dx.doi.org/10.1186/s13023-022-02469-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Hornby, Brittany
Thompson, William Reid
Almuqbil, Mohammed
Manuel, Ryan
Abbruscato, Anthony
Carr, Jim
Vernon, Hilary J.
Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome
title Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome
title_full Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome
title_fullStr Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome
title_full_unstemmed Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome
title_short Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome
title_sort natural history comparison study to assess the efficacy of elamipretide in patients with barth syndrome
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9438322/
https://www.ncbi.nlm.nih.gov/pubmed/36056411
http://dx.doi.org/10.1186/s13023-022-02469-5
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