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Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for Hemophilia A

Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for Hemophilia A
Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for Hemophilia A

BACKGROUND Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. METHODS We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. RESULTS Three years after infusion, two participants (one who had received 6×10 12 vector genomes [vg] per kilogram of body weight and one who had received 2×10 13 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 13 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 13 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. CONCLUSIONS Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 13 vg per kilogram or 6×10 13 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).

0028-4793
29-40
Pasi, K. John
3b81e0be-6e79-4b71-95c5-45fe04b8e6dc
Rangarajan, Savita
9a5e4c7e-55ba-4a3a-b5f6-f1e269d927c3
Mitchell, Nina
adad2cd4-e546-4fd5-8541-9b5952913ab0
Lester, Will
78e4020c-cf87-468f-9122-f7b9dc725af5
Symington, Emily
989a669a-0faf-4b14-a254-ae96c9a80fc7
Madan, Bella
07764bfb-5273-4846-9811-2d730e72c3cf
Laffan, Michael
f22012e7-7ff1-43c2-9520-bbf020428401
Russell, Chris B.
2d51c4cf-da32-46fb-b987-90e06a3703de
Li, Mingjin
a1aefa20-c9dc-4bac-ac71-510987ea2dfe
Pierce, Glenn F.
fa4102f0-d5f8-465b-bb17-7b7e111225d1
Wong, Wing Y.
a2a49aed-413a-4192-b9df-b97acb4cd066
Pasi, K. John
3b81e0be-6e79-4b71-95c5-45fe04b8e6dc
Rangarajan, Savita
9a5e4c7e-55ba-4a3a-b5f6-f1e269d927c3
Mitchell, Nina
adad2cd4-e546-4fd5-8541-9b5952913ab0
Lester, Will
78e4020c-cf87-468f-9122-f7b9dc725af5
Symington, Emily
989a669a-0faf-4b14-a254-ae96c9a80fc7
Madan, Bella
07764bfb-5273-4846-9811-2d730e72c3cf
Laffan, Michael
f22012e7-7ff1-43c2-9520-bbf020428401
Russell, Chris B.
2d51c4cf-da32-46fb-b987-90e06a3703de
Li, Mingjin
a1aefa20-c9dc-4bac-ac71-510987ea2dfe
Pierce, Glenn F.
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Wong, Wing Y.
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Pasi, K. John, Rangarajan, Savita, Mitchell, Nina, Lester, Will, Symington, Emily, Madan, Bella, Laffan, Michael, Russell, Chris B., Li, Mingjin, Pierce, Glenn F. and Wong, Wing Y. (2020) Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for Hemophilia A. New England Journal of Medicine, 382 (1), 29-40. (doi:10.1056/NEJMoa1908490).

Record type: Article

Abstract

BACKGROUND Adeno-associated virus (AAV)-mediated gene therapy is under investigation as a therapeutic option for persons with hemophilia A. Efficacy and safety data include 3 years of follow-up after a single administration of AAV5-hFVIII-SQ. METHODS We report durable efficacy, long-term safety, and clinical and biologic results in 15 adults with severe hemophilia A (factor VIII level, ≤1 IU per deciliter) who had received a single infusion of AAV5-hFVIII-SQ at various dose levels. We evaluated the factor VIII level, annualized rate of bleeding events, use of factor VIII, safety, expression kinetics, and biologic markers of AAV transduction for up to 3 years. RESULTS Three years after infusion, two participants (one who had received 6×10 12 vector genomes [vg] per kilogram of body weight and one who had received 2×10 13 vg per kilogram) had factor VIII expression of less than 1 IU per deciliter, as assessed on chromogenic assay. Seven participants (who had received 6×10 13 vg per kilogram) had a median factor VIII expression of 20 IU per deciliter; the median number of annualized treated bleeding events was 0, and the median use of exogenous factor VIII was reduced from 138.5 infusions to 0 infusions per year. Bleeding in all target joints (major joints with ≥3 bleeding events within 6 months) in this cohort resolved (≤2 bleeding events within 12 months). Two years after infusion, six participants (who had received 4×10 13 vg per kilogram) had a median factor VIII expression of 13 IU per deciliter; the median annualized rate of bleeding events was 0, and the median use of factor VIII was reduced from 155.5 infusions to 0.5 infusions per year. Bleeding in target joints resolved in five of six participants. The factor VIII pharmacodynamic profiles reflected cellular turnover in the blood and molecular events leading to episomal DNA stabilization for persistent expression, findings that are consistent with previous observations in two model systems. Transgene-derived human factor VIII (hFVIII) protein activity mirrored native hFVIII in hemostatic ability. No inhibitor development, thromboses, deaths, or persistent changes in liver-function tests were observed. CONCLUSIONS Gene therapy with AAV5-hFVIII-SQ vector in participants with hemophilia A resulted in sustained, clinically relevant benefit, as measured by a substantial reduction in annualized rates of bleeding events and complete cessation of prophylactic factor VIII use in all participants who had received 4×10 13 vg per kilogram or 6×10 13 vg per kilogram of the gene therapy. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795; EudraCT number, 2014-003880-38.).

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More information

Accepted/In Press date: 1 April 2016
e-pub ahead of print date: 2 January 2020
Published date: 2 January 2020

Identifiers

Local EPrints ID: 442594
URI: http://eprints.soton.ac.uk/id/eprint/442594
ISSN: 0028-4793
PURE UUID: e1d87050-105a-49d9-a8f2-f8d3bb770136
ORCID for Savita Rangarajan: ORCID iD orcid.org/0000-0001-7367-133X

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Date deposited: 20 Jul 2020 16:36
Last modified: 06 Jun 2024 02:08

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Contributors

Author: K. John Pasi
Author: Nina Mitchell
Author: Will Lester
Author: Emily Symington
Author: Bella Madan
Author: Michael Laffan
Author: Chris B. Russell
Author: Mingjin Li
Author: Glenn F. Pierce
Author: Wing Y. Wong

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