FIRST RESULTS FROM A DOSE-ESCALATING STUDY WITH AAV5 VECTOR CONTAINING WILD TYPE HUMAN FACTOR IX GENE THERAPY IN PATIENTS WITH SEVERE OR MODERATELY-SEVERE HAEMOPHILIA B
Author(s): ,
FWG Leebeek
Affiliations:
Erasmus MC,Rotterdam,Netherlands
,
J Schwaeble
Affiliations:
Universitätsklinikum Frankfurt,Frankfurt,Germany
,
K Meijer
Affiliations:
University Medical Center Groningen,Groningen,Netherlands
,
M Coppens
Affiliations:
Academic Medical Center,Amsterdam,Netherlands
,
P Kampmann
Affiliations:
Rigshospitalet,Copenhagen,Denmark
,
S Krekeler
Affiliations:
Universitätsklinikum Frankfurt,Frankfurt,Germany
,
H Bonig
Affiliations:
Universitätsklinikum Frankfurt,Frankfurt,Germany
,
E Seifried
Affiliations:
Universitätsklinikum Frankfurt,Frankfurt,Germany
W Miesbach
Affiliations:
Universitätsklinikum Frankfurt,Frankfurt,Germany
EHA Library. W.G. Leebeek F. 06/11/16; 135223; S467
Dr. Frank W.G. Leebeek
Dr. Frank W.G. Leebeek
Contributions
Abstract
Abstract: S467

Type: Oral Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 11:30 - 11:45

Location: Room H4

Background
Gene therapy for haemophilia B offers the potential to convert the disease severity from severe to a mild phenotype through continuous endogenous production of FIX. Adeno-associated viral (AAV) vectors of serotypes 2 and 8 (AAV2 and AAV8) containing the human factor IX (hFIX) gene have been used in previous clinical trials.1-3 A single infusion with AAV8 vector resulted in dose dependent FIX expression for up to 4 years.4 AMT-060 (AAV5-hFIX) consists of an AAV5 vector with an LP1 liver specific promotor, containing a codon-optimised wild type hFIX gene. A potential advantage of AAV5 is the lower prevalence of neutralising antibodies compared to other serotypes.

Aims
This study aims to investigate the safety and efficacy of AMT-060 in adult patients with severe or moderately severe haemophilia B. 

Methods
This is an open-label, single dose escalating study in patients with FIX activity ≤ 1-2% of normal, and a severe bleeding phenotype. Five patients were enrolled in the first cohort of AMT-060 5x 1012 gc/kg and a subsequent 5 patients will be enrolled in the second cohort of 2 × 1013 gc/kg. Patients receive AMT-060 via IV infusion over 30 minutes in an in-hospital setting.  Safety assessments include treatment related adverse events (AEs) and serious AEs (SAEs). Efficacy assessments include FIX activity, rFIX usage and annualized bleeding rates. We report here preliminary results of the 5 patients treated in the first dose cohort. All patients gave informed consent.

Results
The age of the patients ranged from 35 to 72 years. None of the patients had pre-existing AAV5 antibodies. Four patients had documented FIX activity of <1% and one patient had 1.5%. Four patients had documented haemophiliac arthropathy. All patients were receiving rFIX prophylaxis weekly or twice-weekly prior to treatment with AMT-060. As expected, all 5 patients developed anti-AAV5 antibodies in response to study drug. None of the patients have developed inhibitory antibodies against FIX. Two SAEs have occurred. One patient had an asymptomatic, mild, transient elevation of ALT (peak level at week 10, 61 IU/L; upper limit of normal, 40 IU/L) that resolved after rapid institution of a tapering regimen of prednisolone. Another patient had a self-resolving febrile episode within the first 24 hours of AMT-060 administration.  During the first 12 weeks post-gene therapy, 4 out of the 5 patients achieved FIX activity levels that allowed them to discontinue rFIX prophylaxis. FIX activity and other efficacy outcome measures for a minimum of 30 weeks follow-up of the 5 patients in the first dose cohort will be presented.

Conclusion
Treatment of haemophilia B with a single infusion of AMT-060 was well tolerated, and clinically relevant FIX activity has been achieved in the first dose cohort, relieving 4 out of 5 patients from rFIX prophylaxis. The study will continue with enrolment of the second dose cohort as planned. References1.     Manno C, Chew A, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe haemophilia B. Blood 2003;101:2963-2972.2.     Manno C, Pierce G, Arruda V, et al. Successful transduction of liver in haemophilia by AAV factor IX and limitations imposed by the host immune response. Nat Med 2006;12:342‑347.3.     Nathwani A, Tuddenham E, Rangarajan S, et al. Adenovirus-associated virus vector‑mediated gene transfer in haemophilia B. N Engl J Med 2011;365:2357-2365.4.     Nathwani A, Reiss U, Tuddenham E, et al. Long-term safety and efficacy of factor IX gene therapy in haemophilia B. N Engl J Med 2014;371:1994-2004.

Session topic: Bleeding disorders

Keyword(s): Factor IX, Gene therapy, Hemophilia B
Abstract: S467

Type: Oral Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 11:30 - 11:45

Location: Room H4

Background
Gene therapy for haemophilia B offers the potential to convert the disease severity from severe to a mild phenotype through continuous endogenous production of FIX. Adeno-associated viral (AAV) vectors of serotypes 2 and 8 (AAV2 and AAV8) containing the human factor IX (hFIX) gene have been used in previous clinical trials.1-3 A single infusion with AAV8 vector resulted in dose dependent FIX expression for up to 4 years.4 AMT-060 (AAV5-hFIX) consists of an AAV5 vector with an LP1 liver specific promotor, containing a codon-optimised wild type hFIX gene. A potential advantage of AAV5 is the lower prevalence of neutralising antibodies compared to other serotypes.

Aims
This study aims to investigate the safety and efficacy of AMT-060 in adult patients with severe or moderately severe haemophilia B. 

Methods
This is an open-label, single dose escalating study in patients with FIX activity ≤ 1-2% of normal, and a severe bleeding phenotype. Five patients were enrolled in the first cohort of AMT-060 5x 1012 gc/kg and a subsequent 5 patients will be enrolled in the second cohort of 2 × 1013 gc/kg. Patients receive AMT-060 via IV infusion over 30 minutes in an in-hospital setting.  Safety assessments include treatment related adverse events (AEs) and serious AEs (SAEs). Efficacy assessments include FIX activity, rFIX usage and annualized bleeding rates. We report here preliminary results of the 5 patients treated in the first dose cohort. All patients gave informed consent.

Results
The age of the patients ranged from 35 to 72 years. None of the patients had pre-existing AAV5 antibodies. Four patients had documented FIX activity of <1% and one patient had 1.5%. Four patients had documented haemophiliac arthropathy. All patients were receiving rFIX prophylaxis weekly or twice-weekly prior to treatment with AMT-060. As expected, all 5 patients developed anti-AAV5 antibodies in response to study drug. None of the patients have developed inhibitory antibodies against FIX. Two SAEs have occurred. One patient had an asymptomatic, mild, transient elevation of ALT (peak level at week 10, 61 IU/L; upper limit of normal, 40 IU/L) that resolved after rapid institution of a tapering regimen of prednisolone. Another patient had a self-resolving febrile episode within the first 24 hours of AMT-060 administration.  During the first 12 weeks post-gene therapy, 4 out of the 5 patients achieved FIX activity levels that allowed them to discontinue rFIX prophylaxis. FIX activity and other efficacy outcome measures for a minimum of 30 weeks follow-up of the 5 patients in the first dose cohort will be presented.

Conclusion
Treatment of haemophilia B with a single infusion of AMT-060 was well tolerated, and clinically relevant FIX activity has been achieved in the first dose cohort, relieving 4 out of 5 patients from rFIX prophylaxis. The study will continue with enrolment of the second dose cohort as planned. References1.     Manno C, Chew A, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe haemophilia B. Blood 2003;101:2963-2972.2.     Manno C, Pierce G, Arruda V, et al. Successful transduction of liver in haemophilia by AAV factor IX and limitations imposed by the host immune response. Nat Med 2006;12:342‑347.3.     Nathwani A, Tuddenham E, Rangarajan S, et al. Adenovirus-associated virus vector‑mediated gene transfer in haemophilia B. N Engl J Med 2011;365:2357-2365.4.     Nathwani A, Reiss U, Tuddenham E, et al. Long-term safety and efficacy of factor IX gene therapy in haemophilia B. N Engl J Med 2014;371:1994-2004.

Session topic: Bleeding disorders

Keyword(s): Factor IX, Gene therapy, Hemophilia B

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