© The American Society of Gene & Cell Therapy
editorial
doi:10.1038/mt.2016.98
ADA-SCID Gene Therapy Endorsed by European Medicines Agency for Marketing Authorization
T
he Committee for Human Medicinal Prod-
ucts has recently recommended marketing authorization for retrovirus-mediated ex vivo gene therapy of patients’ autologous CD34+ cells transduced with human ADA complementary DNA for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID).1 If confirmed by the European Commission, the product, called Strimvelis, would be the third approved gene therapy in the European Union. According to the CHMP opinion, “Strimvelis is indicated for the treatment of patients with severe combined immune deficiency due to ADA deficiency (ADASCID), for whom no suitable matched related stem cell donor is available.” The positive opinion includes a request to establish a post-treatment registry and long-term follow-up of the patients. ADA-SCID is a very rare genetic disorder leading to severe deficiency of ADA, which is required for the normal development and function of the immune system.2 Newborns with ADA-SCID cannot fight common infections, and the disease is usually fatal within the first two years of life if left untreated. ADA-SCID is currently treated with bone marrow transplantation from a healthy related donor and with enzyme replacement therapy (ERT). Transplantations from genetically matched siblings have been most successful, but other transplants often lead to graft-versus-host disease. ERT needs to be administered frequently, and long-term efficacy is as yet unreliable. Therefore, a gene therapy–based approach for ADA-SCID patients is most welcome. ADA-SCID was one of the first targets of gene therapy; the first human trials overseen by the National Institutes of Health and in Europe were reported in 1995.3,4 Although the patients were not cured, some engraftment of gene-modified cells was documented. Long-term, dedicated studies by scientists in several research groups5–7 and especially in Milan at the Hospital San Raffaele and Telethon Institute for Gene Therapy, together with the biotechnology company MolMed, led to gradual improvements in the treatment protocol (such Molecular Therapy vol. 24 no. 6 june 2016
as nonmyeloablative preconditioning) and vector production. A subsequent partnership with GlaxoSmithKline in 2010 led to the current positive news from the European Medicines Agency. Strimvelis can produce a long-lasting therapeutic effect after a single treatment. The pivotal clinical study leading to the positive opinion documented a 100% survival rate at 3 years’ follow-up as the primary end point in 12 children. Most (92%) exhibited intervention-free survival without need of ERT or hematopoietic stem cell transplantation for a period >3 months following treatment. A total of 18 children were treated with Strimvelis, and the median follow-up is now approximately 7 years. Safety of the treatment has been acceptable, and a significant reduction in severe infections has been documented, with no leukemic events observed to date.1 The forthcoming approval of ADA-SCID in the European Union is an important milestone in the clinical translation of gene therapy. It represents the first corrective ex vivo gene therapy for children, and the same technology can be applied for gene therapy of several other inherited diseases. ADA-SCID is an ultra-orphan disease, and it is estimated that in the European Union approximately 15 patients will be born every year with this disease. Thus, it will be interesting to see at what price the product will be offered. The benchmark has been set by Glybera, which was the first approved gene therapy in the European Union at approximately US$1 million per patient. However, GlaxoSmithKline has announced that it will permit staged payments for the therapy. Strimvelis treatment will engender considerable logistical problems in collecting and delivering the ex vivo–transduced cells to patients, and the European Medicines Agency suggests that the treatment be administered at specialist transplant centers. Despite these practical concerns, Strimvelis represents a continuation of recent successes of clinical gene transfer, joining Glybera8 and T-VEC9 as the first gene medicines available for human use. 1013
© The American Society of Gene & Cell Therapy
editorial Seppo Ylä-Herttuala Editor-in-Chief
REFERENCES 1.
2.
3.
European Medicines Agency (2016). Summary of opinion. Strimvelis. Autologous CD34+-enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence. . 1 April 2016. Hershfield, MS and Mitchell, BS (2001). Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In: Scriver, CR, Beaudet, AL, Sly, WS and Valle, D (eds). The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill: New York. pp 2585–2625. Blaese, RM, Culver, KW, Miller, AD, Carter, CS, Fleisher, T, Clerici, M et al. (1995). T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270: 475–480.
1014
4.
5.
6.
7.
8. 9.
Bordignon, C, Notarangelo, LD, Nobili, N, Ferrari, G, Casorati, G, Panina, P et al. (1995). Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270: 470–475. Onodera, M, Ariga, T, Kawamura, N, Kobayashi, I, Ohtsu, M, Yamada, M et al. (1998). Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood 91: 30–36. Kohn, DB, Hershfield, MS, Carbonaro, D, Shigeoka, A, Brooks, J, Smogorzewska, EM et al. (1998). T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nat Med 4: 775–780. Aiuti, A, Cattaneo, F, Galimberti, S, Benninghoff, U, Cassani, B, Callegaro, L et al. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360: 447–458. Ylä-Herttuala, S (2012). Endgame: Glybera finally recommended for approval as the first gene therapy drug in the European Union. Mol Ther 20: 1831–1832. Fong, Y (2015). Oncolytic treatment for cancer recommended for approval. Mol Ther 23: 1131.
www.moleculartherapy.org vol. 24 no. 6 june 2016
editorial
doi:10.1038/mt.2016.98
ADA-SCID Gene Therapy Endorsed by European Medicines Agency for Marketing Authorization
T
he Committee for Human Medicinal Prod-
ucts has recently recommended marketing authorization for retrovirus-mediated ex vivo gene therapy of patients’ autologous CD34+ cells transduced with human ADA complementary DNA for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID).1 If confirmed by the European Commission, the product, called Strimvelis, would be the third approved gene therapy in the European Union. According to the CHMP opinion, “Strimvelis is indicated for the treatment of patients with severe combined immune deficiency due to ADA deficiency (ADASCID), for whom no suitable matched related stem cell donor is available.” The positive opinion includes a request to establish a post-treatment registry and long-term follow-up of the patients. ADA-SCID is a very rare genetic disorder leading to severe deficiency of ADA, which is required for the normal development and function of the immune system.2 Newborns with ADA-SCID cannot fight common infections, and the disease is usually fatal within the first two years of life if left untreated. ADA-SCID is currently treated with bone marrow transplantation from a healthy related donor and with enzyme replacement therapy (ERT). Transplantations from genetically matched siblings have been most successful, but other transplants often lead to graft-versus-host disease. ERT needs to be administered frequently, and long-term efficacy is as yet unreliable. Therefore, a gene therapy–based approach for ADA-SCID patients is most welcome. ADA-SCID was one of the first targets of gene therapy; the first human trials overseen by the National Institutes of Health and in Europe were reported in 1995.3,4 Although the patients were not cured, some engraftment of gene-modified cells was documented. Long-term, dedicated studies by scientists in several research groups5–7 and especially in Milan at the Hospital San Raffaele and Telethon Institute for Gene Therapy, together with the biotechnology company MolMed, led to gradual improvements in the treatment protocol (such Molecular Therapy vol. 24 no. 6 june 2016
as nonmyeloablative preconditioning) and vector production. A subsequent partnership with GlaxoSmithKline in 2010 led to the current positive news from the European Medicines Agency. Strimvelis can produce a long-lasting therapeutic effect after a single treatment. The pivotal clinical study leading to the positive opinion documented a 100% survival rate at 3 years’ follow-up as the primary end point in 12 children. Most (92%) exhibited intervention-free survival without need of ERT or hematopoietic stem cell transplantation for a period >3 months following treatment. A total of 18 children were treated with Strimvelis, and the median follow-up is now approximately 7 years. Safety of the treatment has been acceptable, and a significant reduction in severe infections has been documented, with no leukemic events observed to date.1 The forthcoming approval of ADA-SCID in the European Union is an important milestone in the clinical translation of gene therapy. It represents the first corrective ex vivo gene therapy for children, and the same technology can be applied for gene therapy of several other inherited diseases. ADA-SCID is an ultra-orphan disease, and it is estimated that in the European Union approximately 15 patients will be born every year with this disease. Thus, it will be interesting to see at what price the product will be offered. The benchmark has been set by Glybera, which was the first approved gene therapy in the European Union at approximately US$1 million per patient. However, GlaxoSmithKline has announced that it will permit staged payments for the therapy. Strimvelis treatment will engender considerable logistical problems in collecting and delivering the ex vivo–transduced cells to patients, and the European Medicines Agency suggests that the treatment be administered at specialist transplant centers. Despite these practical concerns, Strimvelis represents a continuation of recent successes of clinical gene transfer, joining Glybera8 and T-VEC9 as the first gene medicines available for human use. 1013
© The American Society of Gene & Cell Therapy
editorial Seppo Ylä-Herttuala Editor-in-Chief
REFERENCES 1.
2.
3.
European Medicines Agency (2016). Summary of opinion. Strimvelis. Autologous CD34+-enriched cell fraction that contains CD34+ cells transduced with retroviral vector that encodes for the human ADA cDNA sequence. . 1 April 2016. Hershfield, MS and Mitchell, BS (2001). Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In: Scriver, CR, Beaudet, AL, Sly, WS and Valle, D (eds). The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill: New York. pp 2585–2625. Blaese, RM, Culver, KW, Miller, AD, Carter, CS, Fleisher, T, Clerici, M et al. (1995). T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science 270: 475–480.
1014
4.
5.
6.
7.
8. 9.
Bordignon, C, Notarangelo, LD, Nobili, N, Ferrari, G, Casorati, G, Panina, P et al. (1995). Gene therapy in peripheral blood lymphocytes and bone marrow for ADA-immunodeficient patients. Science 270: 470–475. Onodera, M, Ariga, T, Kawamura, N, Kobayashi, I, Ohtsu, M, Yamada, M et al. (1998). Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency. Blood 91: 30–36. Kohn, DB, Hershfield, MS, Carbonaro, D, Shigeoka, A, Brooks, J, Smogorzewska, EM et al. (1998). T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nat Med 4: 775–780. Aiuti, A, Cattaneo, F, Galimberti, S, Benninghoff, U, Cassani, B, Callegaro, L et al. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 360: 447–458. Ylä-Herttuala, S (2012). Endgame: Glybera finally recommended for approval as the first gene therapy drug in the European Union. Mol Ther 20: 1831–1832. Fong, Y (2015). Oncolytic treatment for cancer recommended for approval. Mol Ther 23: 1131.
www.moleculartherapy.org vol. 24 no. 6 june 2016
