PMID- 32915950
OWN - NLM
STAT- MEDLINE
DCOM- 20210406
LR  - 20211204
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 136
IP  - 22
DP  - 2020 Nov 26
TI  - Activity of transgene-produced B-domain-deleted factor VIII in human plasma 
      following AAV5 gene therapy.
PG  - 2524-2534
LID - 10.1182/blood.2020005683 [doi]
AB  - Adeno-associated virus (AAV)-based gene therapies can restore endogenous factor 
      VIII (FVIII) expression in hemophilia A (HA). AAV vectors typically use a 
      B-domain-deleted FVIII transgene, such as human FVIII-SQ in valoctocogene 
      roxaparvovec (AAV5-FVIII-SQ). Surprisingly, the activity of transgene-produced 
      FVIII-SQ was between 1.3 and 2.0 times higher in one-stage clot (OS) assays than 
      in chromogenic-substrate (CS) assays, whereas recombinant FVIII-SQ products had 
      lower OS than CS activity. Transgene-produced and recombinant FVIII-SQ showed 
      comparable specific activity (international units per milligram) in the CS assay, 
      demonstrating that the diverging activities arise in the OS assay. Higher OS 
      activity for transgene-produced FVIII-SQ was observed across various assay kits 
      and clinical laboratories, suggesting that intrinsic molecular features are 
      potential root causes. Further experiments in 2 participants showed that 
      transgene-produced FVIII-SQ accelerated early factor Xa and thrombin formation, 
      which may explain the higher OS activity based on a kinetic bias between OS and 
      CS assay readout times. Despite the faster onset of coagulation, global thrombin 
      levels were unaffected. A correlation with joint bleeds suggested that both OS 
      and CS assay remained clinically meaningful to distinguish hemophilic from 
      nonhemophilic FVIII activity levels. During clinical development, the CS activity 
      was chosen as a surrogate end point to conservatively assess hemostatic efficacy 
      and enable comparison with recombinant FVIII-SQ products. Relevant trials are 
      registered on clinicaltrials.gov as #NCT02576795 and #NCT03370913 and, 
      respectively, on EudraCT (European Union Drug Regulating Authorities Clinical 
      Trials Database; https://eudract.ema.europa.eu) as #2014-003880-38 and 
      #2017-003215-19.
CI  - (c) 2020 by The American Society of Hematology.
FAU - Rosen, Steffen
AU  - Rosen S
AD  - Rossix AB, Molndal, Sweden.
FAU - Tiefenbacher, Stefan
AU  - Tiefenbacher S
AD  - Colorado Coagulation, Laboratory Corporation of America Holdings, Englewood, CO.
FAU - Robinson, Mary
AU  - Robinson M
AD  - Colorado Coagulation, Laboratory Corporation of America Holdings, Englewood, CO.
FAU - Huang, Mei
AU  - Huang M
AD  - BioMarin Pharmaceutical Inc, Novato, CA.
FAU - Srimani, Jaydeep
AU  - Srimani J
AD  - BioMarin Pharmaceutical Inc, Novato, CA.
FAU - Mackenzie, Donnie
AU  - Mackenzie D
AD  - BioMarin Pharmaceutical Inc, Novato, CA.
FAU - Christianson, Terri
AU  - Christianson T
AD  - BioMarin Pharmaceutical Inc, Novato, CA.
FAU - Pasi, K John
AU  - Pasi KJ
AD  - Royal London Haemophilia Centre, Barts Health, National Health Service (NHS) 
      Trust, London, United Kingdom.
FAU - Rangarajan, Savita
AU  - Rangarajan S
AD  - University Hospital Southampton, Southampton, United Kingdom.
FAU - Symington, Emily
AU  - Symington E
AD  - Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom.
FAU - Giermasz, Adam
AU  - Giermasz A
AD  - Division of Hematology/Oncology, Department of Medicine, University of California 
      at Davis, Sacramento, CA; and.
FAU - Pierce, Glenn F
AU  - Pierce GF
AD  - Independent Consultant.
FAU - Kim, Benjamin
AU  - Kim B
AD  - BioMarin Pharmaceutical Inc, Novato, CA.
FAU - Zoog, Stephen J
AU  - Zoog SJ
AD  - BioMarin Pharmaceutical Inc, Novato, CA.
FAU - Vettermann, Christian
AU  - Vettermann C
AD  - BioMarin Pharmaceutical Inc, Novato, CA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03370913
SI  - ClinicalTrials.gov/NCT02576795
SI  - EudraCT/2014-003880-38
SI  - EudraCT/2017-003215-19
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 113E3Z3CJJ (recombinant factor VIII SQ)
RN  - 839MOZ74GK (F8 protein, human)
RN  - 9001-27-8 (Factor VIII)
RN  - Adeno-associated virus-5
SB  - IM
CIN - Blood. 2020 Nov 26;136(22):2483-2484. PMID: 33242331
MH  - Dependovirus
MH  - *Factor VIII/genetics/metabolism
MH  - *Genetic Therapy
MH  - *Hemophilia A/blood/genetics/therapy
MH  - Humans
MH  - Male
MH  - *Parvovirinae
MH  - *Transgenes
PMC - PMC7714098
COIS- Conflict-of-interest disclosure: S. Rosen is chairman of Rossix AB. S.T. and M.R. 
      are employees and hold stock in Laboratory Corporation of America Holdings. S. 
      Rosen and G.F.P. are consultants for BioMarin Pharmaceutical Inc. M.H., J.S., 
      D.M., T.C., B.K., S.J.Z., and C.V. are employees and own stock in BioMarin 
      Pharmaceutical Inc. The remaining authors declare no competing financial 
      interests.
EDAT- 2020/09/12 06:00
MHDA- 2021/04/07 06:00
PMCR- 2020/11/26
CRDT- 2020/09/11 17:13
PHST- 2020/03/06 00:00 [received]
PHST- 2020/08/25 00:00 [accepted]
PHST- 2020/09/12 06:00 [pubmed]
PHST- 2021/04/07 06:00 [medline]
PHST- 2020/09/11 17:13 [entrez]
PHST- 2020/11/26 00:00 [pmc-release]
AID - S0006-4971(20)81978-8 [pii]
AID - 2020/BLD2020005683 [pii]
AID - 10.1182/blood.2020005683 [doi]
PST - ppublish
SO  - Blood. 2020 Nov 26;136(22):2524-2534. doi: 10.1182/blood.2020005683.