Long-term safety and efficacy of factor IX gene therapy in hemophilia B

Amit C. Nathwani, U. M. Reiss, E. G D Tuddenham, C. Rosales, P. Chowdary, J. McIntosh, M. Della Peruta, E. Lheriteau, N. Patel, D. Raj, A. Riddell, J. Pie, S. Rangarajan, D. Bevan, Michael Recht, Y. M. Shen, K. G. Halka, E. Basner-Tschakarjan, F. Mingozzi, K. A. HighJ. Allay, M. A. Kay, C. Y C Ng, J. Zhou, M. Cancio, C. L. Morton, J. T. Gray, D. Srivastava, A. W. Nienhuis, A. M. Davidoff

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported.

Original languageEnglish (US)
Pages (from-to)1994-2004
Number of pages11
JournalNew England Journal of Medicine
Volume371
Issue number21
DOIs
StatePublished - Nov 20 2014

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Hemophilia B
Factor IX
Genetic Therapy
Safety
Dependovirus
Transgenes
Poisons
Prednisolone
Alanine Transaminase
Intravenous Infusions
Reference Values
Therapeutics
Body Weight
Observation
Genome
Hemorrhage

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nathwani, A. C., Reiss, U. M., Tuddenham, E. G. D., Rosales, C., Chowdary, P., McIntosh, J., ... Davidoff, A. M. (2014). Long-term safety and efficacy of factor IX gene therapy in hemophilia B. New England Journal of Medicine, 371(21), 1994-2004. https://doi.org/10.1056/NEJMoa1407309

Long-term safety and efficacy of factor IX gene therapy in hemophilia B. / Nathwani, Amit C.; Reiss, U. M.; Tuddenham, E. G D; Rosales, C.; Chowdary, P.; McIntosh, J.; Della Peruta, M.; Lheriteau, E.; Patel, N.; Raj, D.; Riddell, A.; Pie, J.; Rangarajan, S.; Bevan, D.; Recht, Michael; Shen, Y. M.; Halka, K. G.; Basner-Tschakarjan, E.; Mingozzi, F.; High, K. A.; Allay, J.; Kay, M. A.; Ng, C. Y C; Zhou, J.; Cancio, M.; Morton, C. L.; Gray, J. T.; Srivastava, D.; Nienhuis, A. W.; Davidoff, A. M.

In: New England Journal of Medicine, Vol. 371, No. 21, 20.11.2014, p. 1994-2004.

Research output: Contribution to journalArticle

Nathwani, AC, Reiss, UM, Tuddenham, EGD, Rosales, C, Chowdary, P, McIntosh, J, Della Peruta, M, Lheriteau, E, Patel, N, Raj, D, Riddell, A, Pie, J, Rangarajan, S, Bevan, D, Recht, M, Shen, YM, Halka, KG, Basner-Tschakarjan, E, Mingozzi, F, High, KA, Allay, J, Kay, MA, Ng, CYC, Zhou, J, Cancio, M, Morton, CL, Gray, JT, Srivastava, D, Nienhuis, AW & Davidoff, AM 2014, 'Long-term safety and efficacy of factor IX gene therapy in hemophilia B', New England Journal of Medicine, vol. 371, no. 21, pp. 1994-2004. https://doi.org/10.1056/NEJMoa1407309
Nathwani AC, Reiss UM, Tuddenham EGD, Rosales C, Chowdary P, McIntosh J et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. New England Journal of Medicine. 2014 Nov 20;371(21):1994-2004. https://doi.org/10.1056/NEJMoa1407309
Nathwani, Amit C. ; Reiss, U. M. ; Tuddenham, E. G D ; Rosales, C. ; Chowdary, P. ; McIntosh, J. ; Della Peruta, M. ; Lheriteau, E. ; Patel, N. ; Raj, D. ; Riddell, A. ; Pie, J. ; Rangarajan, S. ; Bevan, D. ; Recht, Michael ; Shen, Y. M. ; Halka, K. G. ; Basner-Tschakarjan, E. ; Mingozzi, F. ; High, K. A. ; Allay, J. ; Kay, M. A. ; Ng, C. Y C ; Zhou, J. ; Cancio, M. ; Morton, C. L. ; Gray, J. T. ; Srivastava, D. ; Nienhuis, A. W. ; Davidoff, A. M. / Long-term safety and efficacy of factor IX gene therapy in hemophilia B. In: New England Journal of Medicine. 2014 ; Vol. 371, No. 21. pp. 1994-2004.
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abstract = "BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6{\%} of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7{\%} was observed in all 6 patients, which resulted in a reduction of more than 90{\%} in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported.",
author = "Nathwani, {Amit C.} and Reiss, {U. M.} and Tuddenham, {E. G D} and C. Rosales and P. Chowdary and J. McIntosh and {Della Peruta}, M. and E. Lheriteau and N. Patel and D. Raj and A. Riddell and J. Pie and S. Rangarajan and D. Bevan and Michael Recht and Shen, {Y. M.} and Halka, {K. G.} and E. Basner-Tschakarjan and F. Mingozzi and High, {K. A.} and J. Allay and Kay, {M. A.} and Ng, {C. Y C} and J. Zhou and M. Cancio and Morton, {C. L.} and Gray, {J. T.} and D. Srivastava and Nienhuis, {A. W.} and Davidoff, {A. M.}",
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T1 - Long-term safety and efficacy of factor IX gene therapy in hemophilia B

AU - Nathwani, Amit C.

AU - Reiss, U. M.

AU - Tuddenham, E. G D

AU - Rosales, C.

AU - Chowdary, P.

AU - McIntosh, J.

AU - Della Peruta, M.

AU - Lheriteau, E.

AU - Patel, N.

AU - Raj, D.

AU - Riddell, A.

AU - Pie, J.

AU - Rangarajan, S.

AU - Bevan, D.

AU - Recht, Michael

AU - Shen, Y. M.

AU - Halka, K. G.

AU - Basner-Tschakarjan, E.

AU - Mingozzi, F.

AU - High, K. A.

AU - Allay, J.

AU - Kay, M. A.

AU - Ng, C. Y C

AU - Zhou, J.

AU - Cancio, M.

AU - Morton, C. L.

AU - Gray, J. T.

AU - Srivastava, D.

AU - Nienhuis, A. W.

AU - Davidoff, A. M.

PY - 2014/11/20

Y1 - 2014/11/20

N2 - BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported.

AB - BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×1012 vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported.

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