TY - JOUR
T1 - Gene therapy with adeno-associated virus vector 5–human factor IX in adults with hemophilia B
AU - Miesbach, Wolfgang
AU - Meijer, Karina
AU - Coppens, Michiel
AU - Kampmann, Peter
AU - Klamroth, Robert
AU - Schutgens, Roger
AU - Tangelder, Marco
AU - Castaman, Giancarlo
AU - Schwäble, Joachim
AU - Bonig, Halvard
AU - Seifried, Erhard
AU - Cattaneo, Federica
AU - Meyer, Christian
AU - Leebeek, Frank W.G.
N1 - Funding Information:
This work was supported by uniQure, which provided funding for writing support, provided by Mike Lappin of GK Pharmacomm Ltd. Eileen Sawyer, a uniQure employee, provided critical feedback on the manuscript.
Funding Information:
Conflict-of-interest disclosure: W.M. reports receiving consultant fees from uniQure B.V. during the conduct of the study; grants and personal fees from Novo Nordisk; and personal fees from Bayer, Shire, Biotest, Pfizer, Octapharma, LFB, CSL Behring, SOBI, Biogen, and BPL outside of the submitted work. K.M. reports receiving consulting fees from uniQure B.V. during the conduct of the study and has received travel support from Baxter and Pfizer; travel support and speaker fees from Bayer and Sanquin; and speaker fees from Boehringer Ingelheim, BMS, and Aspen outside of the submitted work. M.C. reports receiving consultant fees from uniQure B.V. during the conduct of the study and has received grants, personal fees, and nonfinancial support from CSL Behring and Bayer outside of the submitted work. P.K. reports receiving a trial-related fee from uniQure B.V. during the conduct of the study. R.K. reports receiving grants and personal fees from Shire/Baxalta, Bayer, CSL Behring, and Pfizer outside of the submitted work; and personal fees from SOBI, Biotest, Chiesi, Octapharma, and Novo Nordisk outside of the submitted work. R.S. reports receiving financial support from uniQure B.V. paid to his institution during the conduct of the study. At the time of contributing, M.T. was a uniQure employee. G.C. reports receiving a trial-related fee from uniQure B.V. during the conduct of the study, and personal fees from Novo Nordisk, Shire, Sobi, CSL Behring, Pfizer, and Bayer outside of the submitted work. F.C. is a Chiesi Farmaceutici S.p.A. employee. At the time of contributing, C.M. was a uniQure employee. F.W.G.L. reports receiving fees paid to his institution from uniQure B.V. during the conduct of the study, has been a consultant for Shire and Novo Nordisk outside of the submitted work, and has received research grants from CSL Behring and Baxalta/Shire outside of the submitted work. The remaining authors declare no competing conflicts of interest.
Funding Information:
The authors thank the study participants and their families. The authors would also like to thank the following individuals for their assistance with the conduct of the study: L. Landman (Academic Medical Centre Amsterdam); M. J. H. A. Kruip, G. Mulders, P. van der Graaf, R. Bouamar, and C. Bakker (Erasmus University Medical Centre); F. Peyvandi (Fondazione IRCCS Cà Granda Ospedale Maggiore Milan); E. Funding, R. Duus Müller, R. Svensgaard, C. Nielsen, and Mette Nordahl Rahbek (Rigshospitalet Copenhagen); S. Gundermann, K. Scholz, and S. Krekeler (University Hospital Frankfurt am Main); F. Yspeerd, K. Thedinga, M. Voskuilen, B. Molmans, M. Segers, and B. Waarts (University Medical Center Groningen); P. van der Valk, E. J. van Beers, D. Dekker, M. van Haaften-Spoor, S. Oortwijn-De Loo, A. Braem-Enneman, M. Timmer, and H. Aanstoot (University Medical Centre Utrecht); C. Kulick-Hofmann, A. Orlovic, and Y. Limberg (Vivantes Klinikum Berlin); Carolin Poppe (German Red Cross Blood Service, Frankfurt); and Ilse Tuinhof, Corine Baljé-Volkers, and Tatyana De Bruyne (uniQure biopharma B.V.). This work was supported by uniQure, which provided funding for writing support, provided by Mike Lappin of GK Pharmacomm Ltd. Eileen Sawyer, a uniQure employee, provided critical feedback on the manuscript.
Publisher Copyright:
© 2018 by The American Society of Hematology.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX £2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 3 10 12 or 2 3 10 13 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n 5 1) and higher-dose (n 5 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.
AB - Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX £2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 3 10 12 or 2 3 10 13 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n 5 1) and higher-dose (n 5 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.
UR - http://www.scopus.com/inward/record.url?scp=85045912262&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-09-804419
DO - 10.1182/blood-2017-09-804419
M3 - Article
C2 - 29246900
AN - SCOPUS:85045912262
SN - 0006-4971
VL - 131
SP - 1022
EP - 1031
JO - Blood
JF - Blood
IS - 9
ER -