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Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A

INTRODUCTION: Valoctocogene roxaparvovec is an investigational AAV5‐based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. AIM: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received va...

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Autores principales: Pasi, K John, Laffan, Michael, Rangarajan, Savita, Robinson, Tara M, Mitchell, Nina, Lester, Will, Symington, Emily, Madan, Bella, Yang, Xinqun, Kim, Benjamin, Pierce, Glenn F, Wong, Wing Yen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291073/
https://www.ncbi.nlm.nih.gov/pubmed/34378280
http://dx.doi.org/10.1111/hae.14391
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author Pasi, K John
Laffan, Michael
Rangarajan, Savita
Robinson, Tara M
Mitchell, Nina
Lester, Will
Symington, Emily
Madan, Bella
Yang, Xinqun
Kim, Benjamin
Pierce, Glenn F
Wong, Wing Yen
author_facet Pasi, K John
Laffan, Michael
Rangarajan, Savita
Robinson, Tara M
Mitchell, Nina
Lester, Will
Symington, Emily
Madan, Bella
Yang, Xinqun
Kim, Benjamin
Pierce, Glenn F
Wong, Wing Yen
author_sort Pasi, K John
collection PubMed
description INTRODUCTION: Valoctocogene roxaparvovec is an investigational AAV5‐based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. AIM: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795). METHODS: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti‐AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 10(13) vg/kg dose, n = 7) and 4 years (4 × 10(13) vg/kg dose, n = 6). RESULTS: Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 10(13) and 4 × 10(13) vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was ‐0.14 (95% confidence interval [CI]: ‐.32 to .03) IU/dl/wk in the 6 × 10(13) vg/kg cohort in year 5 and ‐.06 (95% CI: ‐.14 to .01) IU/dl/wk in the 4 × 10(13) vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 10(13) vg/kg cohort; all six Haemo‐QOL‐A domain scores increased. For the 4 × 10(13) vg/kg cohort, high baseline Haemo‐QOL‐A scores persisted. CONCLUSION: These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A.
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spelling pubmed-92910732022-07-20 Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A Pasi, K John Laffan, Michael Rangarajan, Savita Robinson, Tara M Mitchell, Nina Lester, Will Symington, Emily Madan, Bella Yang, Xinqun Kim, Benjamin Pierce, Glenn F Wong, Wing Yen Haemophilia Original Articles INTRODUCTION: Valoctocogene roxaparvovec is an investigational AAV5‐based factor VIII (FVIII) gene therapy that has demonstrated sustained clinical benefit in people with severe haemophilia A. AIM: To report safety, tolerability, efficacy, and quality of life (QOL) among participants who received valoctocogene roxaparvovec in a phase 1/2 clinical study (NCT02576795). METHODS: Men ≥18 years of age with severe haemophilia A (FVIII ≤1 IU/dl) without history of FVIII inhibitors or anti‐AAV5 antibodies received a single infusion of valoctocogene roxaparvovec and were followed for 5 years (6 × 10(13) vg/kg dose, n = 7) and 4 years (4 × 10(13) vg/kg dose, n = 6). RESULTS: Over the past 2 years, few adverse events and no FVIII inhibitors were reported. Per chromogenic substrate (CSA) assay at years 5 and 4, four of seven and three of six participants in the 6 × 10(13) and 4 × 10(13) vg/kg cohorts, respectively, maintained median FVIII levels >5 IU/dl, corresponding to mild haemophilia. By regression analysis, rate of change in FVIII activity was ‐0.14 (95% confidence interval [CI]: ‐.32 to .03) IU/dl/wk in the 6 × 10(13) vg/kg cohort in year 5 and ‐.06 (95% CI: ‐.14 to .01) IU/dl/wk in the 4 × 10(13) vg/kg cohort in year 4. No participants resumed FVIII prophylaxis, and eight of 13 participants reported zero bleeds in the past 2 years. Improved QOL from baseline persisted in the 6 × 10(13) vg/kg cohort; all six Haemo‐QOL‐A domain scores increased. For the 4 × 10(13) vg/kg cohort, high baseline Haemo‐QOL‐A scores persisted. CONCLUSION: These results demonstrate transgene expression and haemostatic response for up to 5 years in individuals with haemophilia A. John Wiley and Sons Inc. 2021-08-11 2021-11 /pmc/articles/PMC9291073/ /pubmed/34378280 http://dx.doi.org/10.1111/hae.14391 Text en © 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Articles
Pasi, K John
Laffan, Michael
Rangarajan, Savita
Robinson, Tara M
Mitchell, Nina
Lester, Will
Symington, Emily
Madan, Bella
Yang, Xinqun
Kim, Benjamin
Pierce, Glenn F
Wong, Wing Yen
Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
title Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
title_full Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
title_fullStr Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
title_full_unstemmed Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
title_short Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A
title_sort persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia a
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291073/
https://www.ncbi.nlm.nih.gov/pubmed/34378280
http://dx.doi.org/10.1111/hae.14391
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