Gene therapy for thalassemia
| Product and study name . | Sponsor . | Principle of therapy . | Transgene vector . | Patient target no. and age eligibility . | Cell source mobilization . | BMT conditioning CD34+ infusion dose . | VCN of infused CD34+ . | Outcomes . | Stage of trial development . |
|---|---|---|---|---|---|---|---|---|---|
| HVP569, LG001 | Genetix France | Autologous transplant of transduced CD34+ HSC | β Α−>T 87Q encoding human β-globin (T87Q) LV vector HVP569 | 4 TDT 5-35 y | Bone marrow or peripheral blood | Busulfan 12.8 mg/kg over 4 d; dose adjusted to PK IV 3.9 × 106 CD34/kg BM 4.3 × 106 cells/kg from PB | 0.6 | 1 case of transfusion independence in Eβ thalassemia with stable clone at 7 y FU; low engraftment in 3 other patients | Phase 1 started July 2006 |
| LlentigGlobin BB305 HGB −204 | BBB | As above | As above, with removal of insulator LV vector BB305 | 18 TDT 12-35 y | PB GCSF + plerixafor | Busulfan 12.8 mg/kg 6-18 × 106 CD34/kg β0/β0 5-13 × 106 CD34/kg others | 0.3-1.5 | Interim published; see text | Phase 1/2 started 2013 |
| LlentigGlobin HGB-205 NCT02151526 | BBB | As above | As above | 7 TDT 5-35 y | As above | Busulfan 12.8 mg/kg IV 9-14 × 106 CD34/kg | 0.8-2.1 | Interim published; see text | Phase 1/2 started August 2014 |
| LlentigGlobin HGB −207 | BBB | As above | As above | non β0/β0 n = 15 12-50 y | As above | Busulfan 12.8 mg/kg IV 7-8 × 106 CD34/kg | 2.4-3.2 | Interim results presented at ASH 2017 Transfusion-free 3/3 at >6 mo | Phase 3 |
| LlentigGlobin HGB −212 | BBB | As above | As above + improved manufacturing to increase VCN | β0/β0 n = 4, 3-7 y n = 3, 8-17 y | As above | Busulfan 12.8 mg/kg × 4 d | Ongoing | Ongoing | Phase 3 ongoing |
| Was TNS9.3.55 NCT01639690; now TNS9.3.55.A1 | Memorial Sloan Kettering | Transplant of autologous CD34+ HSC transduced with TNS9 3.55 | Lentiviral vector | 10 TDT >18 y | As above | Reduced intensity conditioning 2 d; busulfan 8 g/kg; interval 2 d IV 11.8-8.4 × 106 CD34/kg | 0.39-0.21 | Stable engraftment without clonal dominance17 | Phase 1 started July 2012; completion July 2018? |
| ST-400 | Sangamo, Bioverativ | Transplant of autologous modified CD34+ HSC | Zinc finger nuclease to boost HbF by disruption of BCL11A gene | 6 TDT 18-40 y | As above | Standard conditioning anticipated | NA | Change in HbF; change in annual volume of packed RBC | Phase 1/2 started May 2018; ends May 2020 |
| TIGET-BTHAL NCT02453477 | Telethon Foundation | Transplant of autologous modified CD34+ HSC | β globin GLOBE | TDT 3/≥18 y 3/8-17 y 4/3-7 y | As above | Treosulfan 42 g/m2 + thiotepa 8 mg/kg 16-19.5 × 106 CD34+/kg intramarrow | 0.7-1.5 | Ongoing | Phase 1/2 Started May 2015 |
| CTX001 | CRISPR Therapeutics and Vertex | Transplant of autologous modified CD34+ HSC | Zinc finger nuclease to boost HbF by disruption of BCL11A gene | TDT (also SCD) | As above | Reduced intensity conditioning 2 d; busulfan 8 mg/kg; interval 2 d 11.8-8.4 × 106 CD34/kg | NA | Change in HbF; change in annual RBC ex vivo; increases in γ-globin mRNA to 39% (as a ratio of γ/α) in 1 β-thalassemia patient sample | Phase 1 beginning in Europe |
| Product and study name . | Sponsor . | Principle of therapy . | Transgene vector . | Patient target no. and age eligibility . | Cell source mobilization . | BMT conditioning CD34+ infusion dose . | VCN of infused CD34+ . | Outcomes . | Stage of trial development . |
|---|---|---|---|---|---|---|---|---|---|
| HVP569, LG001 | Genetix France | Autologous transplant of transduced CD34+ HSC | β Α−>T 87Q encoding human β-globin (T87Q) LV vector HVP569 | 4 TDT 5-35 y | Bone marrow or peripheral blood | Busulfan 12.8 mg/kg over 4 d; dose adjusted to PK IV 3.9 × 106 CD34/kg BM 4.3 × 106 cells/kg from PB | 0.6 | 1 case of transfusion independence in Eβ thalassemia with stable clone at 7 y FU; low engraftment in 3 other patients | Phase 1 started July 2006 |
| LlentigGlobin BB305 HGB −204 | BBB | As above | As above, with removal of insulator LV vector BB305 | 18 TDT 12-35 y | PB GCSF + plerixafor | Busulfan 12.8 mg/kg 6-18 × 106 CD34/kg β0/β0 5-13 × 106 CD34/kg others | 0.3-1.5 | Interim published; see text | Phase 1/2 started 2013 |
| LlentigGlobin HGB-205 NCT02151526 | BBB | As above | As above | 7 TDT 5-35 y | As above | Busulfan 12.8 mg/kg IV 9-14 × 106 CD34/kg | 0.8-2.1 | Interim published; see text | Phase 1/2 started August 2014 |
| LlentigGlobin HGB −207 | BBB | As above | As above | non β0/β0 n = 15 12-50 y | As above | Busulfan 12.8 mg/kg IV 7-8 × 106 CD34/kg | 2.4-3.2 | Interim results presented at ASH 2017 Transfusion-free 3/3 at >6 mo | Phase 3 |
| LlentigGlobin HGB −212 | BBB | As above | As above + improved manufacturing to increase VCN | β0/β0 n = 4, 3-7 y n = 3, 8-17 y | As above | Busulfan 12.8 mg/kg × 4 d | Ongoing | Ongoing | Phase 3 ongoing |
| Was TNS9.3.55 NCT01639690; now TNS9.3.55.A1 | Memorial Sloan Kettering | Transplant of autologous CD34+ HSC transduced with TNS9 3.55 | Lentiviral vector | 10 TDT >18 y | As above | Reduced intensity conditioning 2 d; busulfan 8 g/kg; interval 2 d IV 11.8-8.4 × 106 CD34/kg | 0.39-0.21 | Stable engraftment without clonal dominance17 | Phase 1 started July 2012; completion July 2018? |
| ST-400 | Sangamo, Bioverativ | Transplant of autologous modified CD34+ HSC | Zinc finger nuclease to boost HbF by disruption of BCL11A gene | 6 TDT 18-40 y | As above | Standard conditioning anticipated | NA | Change in HbF; change in annual volume of packed RBC | Phase 1/2 started May 2018; ends May 2020 |
| TIGET-BTHAL NCT02453477 | Telethon Foundation | Transplant of autologous modified CD34+ HSC | β globin GLOBE | TDT 3/≥18 y 3/8-17 y 4/3-7 y | As above | Treosulfan 42 g/m2 + thiotepa 8 mg/kg 16-19.5 × 106 CD34+/kg intramarrow | 0.7-1.5 | Ongoing | Phase 1/2 Started May 2015 |
| CTX001 | CRISPR Therapeutics and Vertex | Transplant of autologous modified CD34+ HSC | Zinc finger nuclease to boost HbF by disruption of BCL11A gene | TDT (also SCD) | As above | Reduced intensity conditioning 2 d; busulfan 8 mg/kg; interval 2 d 11.8-8.4 × 106 CD34/kg | NA | Change in HbF; change in annual RBC ex vivo; increases in γ-globin mRNA to 39% (as a ratio of γ/α) in 1 β-thalassemia patient sample | Phase 1 beginning in Europe |
BM, bone marrow; GCSF, granulocyte colony stimulating factor; PB, peripheral blood; PK, pharmacokinetics; SCD, sickle cell disease.