Hemophilia A gene therapy trial using AAV
| AAV vector . | Study . | Outcomes . | Current status . |
|---|---|---|---|
| BMN 270-201: A Phase 1/2, Dose-Escalation, Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Hemophilia A (NCT02576795) | FVIII expression <3% in the low- and intermediate-dose cohorts. 6e13-vg/kg dose cohort (n = 7), mean FVIII activity at 1, 2, and 3 years of 64 IU/dL, 36 IU/dL, and 33 IU/dL (Chromogenic). 4e13-vg/kg dose cohort (n = 6): FVIII activity at years 1 and 2 = 21 IU/dL and 15 IU/dL, respectively (Chromogenic). >90% reduction in ABR and FVIII concentrate infusion in both groups. | Closed to recruitment. LTFU continues. EU conditional approval granted. | |
| BMN 270-203: A Phase 1/2 Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual FVIII Levels ≤1IU/dL and preexisting Antibodies Against AAV5 (NCT03520712) | Enrolling subjects; no data reported. | ||
| BioMarin (BMN 270; AAV5-hFVIII-SQ valoctocogene roxaparvovec) | BMN 270-205: Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec in Hemophilia A With Active or Prior Inhibitors (NCT04684940) | Enrolling subjects; no data reported. | |
| BMN 270-301: A Phase 3 Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual FVIII Levels ≤1IU/dL (NCT03370913) | FVIII activity levels (N = 132) at ~1 year = 41.9 IU/dL (Chromogenic). 98.6% decline in ABR and 83.8% reduction in FVIII concentrate usage. Transaminitis in 85.8% of the participants. | Target recruitment completed. LTFU continues. Under regulatory review. | |
| BMN 270-302: Phase 3 Study to Evaluate Efficacy/Safety of Valoctocogene Roxaparvovec an AAV Vector-Mediated Gene Transfer of hFVIII at a Dose of 4x1013 vg/kg in Hemophilia A Patients With Residual FVIII Levels ≤1IU/dL Receiving Prophylactic FVIII Infusions (GENEr8-2) (NCT03392974). | Phase 3: closed to recruitment due to lack of interest in the low-vector dose. LTFU continues. | ||
| BMN 270-303: A Phase 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII, With Prophylactic Corticosteroids in Hemophilia A Patients (GENEr8-3) (NCT04323098) | Enrolling subjects; no data reported. | ||
| UCL/AAV8 FVIII V3 peptide instead of B-domain | Gene Therapy for Haemophilia A (GO-8, NCT03001830) | 4 doses under evaluation: 6e11, 2e12, 4e12, or 6e12 vg/kg. Longest follow-up in 2e12-vg/kg dose cohort shows stable expression of FVIII out to 3 years at 15 IU/dL. | Open |
| Spark/Roche (SPK-8011) AAV-LK03-FVIII-SQ | SPK-8011-101: Gene Transfer, Dose-Finding Safety, Tolerability, and Efficacy Study of SPK-8011 (a Recombinant Adeno-Associated Viral Vector With Human Factor VIII Gene) in Individuals With Hemophilia A (NCT03003533) Together With Long-Term Follow-up Study (NCT03432520) | 4 cohorts (N = 18) over 5e11 to 2e12 vg/kg; mean FVIII expression ~12.9% ± 6.9% (1-stage clotting assay); 2 participants lost all expression because of transaminitis refractory to immunosuppression; 91% reduction in ABR; FVIII concentrate usage down by 96.4% | Closed to recruitment. LTFU continues. |
| Spark/Roche (SPK-8016) AAV-FVIII-SQ using a novel capsid | SPK-8016-101: Dose-Finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors (NCT03734588) | Recruitment closed. No data reported. | |
| Pfizer/Sangamo Bioscience (SB-525; giroctocogene fitelparvovec) AAV6 FVIII-SQ | SB-525-1603: A Phase 1/2, Open-Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 (PF-07055480) (Recombinant AAV2/6 Human Factor 8 Gene Therapy) in Adult Subjects With Severe Hemophilia A (Alta Study) (NCT03061201) | 4 cohorts (9e11, 2e12, 1e13, and 3e13 vg/kg; N = 11). Mean FVIII activity: ~43% and 25.7% at years 1 and 2, respectively @ 3e13-vg/kg dose level (N = 5); chromogenic assay. Transaminitis was detected in 5 of the 11 participants. | Closed to recruitment. LTFU continues. |
| C0371004: Phase III. An Open-Label, Non-investigational Product, Lead-in Study to Evaluate at Least 6 Months of Prospective Efficacy and Safety Data of Factor Replacement Therapy in the Usual Care Setting of Moderately Severe to Severe Adult Hemophilia B Subjects (FIX:C ≤2%) Who Are Negative for Nab to AAV Vector-Spark100 and Moderately Severe to Severe Hemophilia A Adult Subjects (FVIII:C ≤1%) Who Are Negative for Nab to AAV Vector Sb-525 Capsid (AAV6), Prior to the Respective Therapeutic Ph 3 Gene Therapy Studies (NAB Protocol) (NCT03587116) | Recruiting 250 subjects in this 6-month lead-in study to support the phase 3 intervention study. | ||
| C3731003: Phase 3, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of PF-07055480 (Recombinant AAV2/6 Human Factor VIII Gene Therapy) in Adult Male Participants With Moderately Severe to Severe Hemophilia A (FVIII:C ≤1%) (AFFINE) (NCT04370054) | Recruitment target = 60 patients. Phase 3 restarted following temporary regulatory hold for high FVIII levels (>150%) in some participants. | ||
| Bayer/Ultragenyx Therapeutics BAY 2599023 (DTX-201) AAVhu37 capsid pseudotyped FVIII-SQ | A Phase 1/2 Open-Label Safety and Dose-Finding Study of BAY2599023 (DTX201), an Adeno-Associated Virus (AAV) hu37-Mediated Gene Transfer of B-Domain Deleted Human Factor VIII, in Adults With Severe Hemophilia A (NCT03588299) | 9 participants enrolled sequentially into 1 of 3 dose cohorts (0.5e13, 1e13, and 2e13 vg/kg). FVIII expression levels for up to >23 months. Transaminitis observed in 5/9 participants. | |
| Takeda (TAK 754) AAV8-FVIII-SQ | A Study of BAX 888 in Male Adults With Severe Hemophilia A (NCT03370172) | 2e12- and 6e12-vg/kg dose cohorts assessed. Study suspended following transaminitis-mediated loss of FVIII expression in all participants. | |
| AAV vector . | Study . | Outcomes . | Current status . |
|---|---|---|---|
| BMN 270-201: A Phase 1/2, Dose-Escalation, Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Hemophilia A (NCT02576795) | FVIII expression <3% in the low- and intermediate-dose cohorts. 6e13-vg/kg dose cohort (n = 7), mean FVIII activity at 1, 2, and 3 years of 64 IU/dL, 36 IU/dL, and 33 IU/dL (Chromogenic). 4e13-vg/kg dose cohort (n = 6): FVIII activity at years 1 and 2 = 21 IU/dL and 15 IU/dL, respectively (Chromogenic). >90% reduction in ABR and FVIII concentrate infusion in both groups. | Closed to recruitment. LTFU continues. EU conditional approval granted. | |
| BMN 270-203: A Phase 1/2 Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual FVIII Levels ≤1IU/dL and preexisting Antibodies Against AAV5 (NCT03520712) | Enrolling subjects; no data reported. | ||
| BioMarin (BMN 270; AAV5-hFVIII-SQ valoctocogene roxaparvovec) | BMN 270-205: Safety, Tolerability, and Efficacy Study of Valoctocogene Roxaparvovec in Hemophilia A With Active or Prior Inhibitors (NCT04684940) | Enrolling subjects; no data reported. | |
| BMN 270-301: A Phase 3 Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Residual FVIII Levels ≤1IU/dL (NCT03370913) | FVIII activity levels (N = 132) at ~1 year = 41.9 IU/dL (Chromogenic). 98.6% decline in ABR and 83.8% reduction in FVIII concentrate usage. Transaminitis in 85.8% of the participants. | Target recruitment completed. LTFU continues. Under regulatory review. | |
| BMN 270-302: Phase 3 Study to Evaluate Efficacy/Safety of Valoctocogene Roxaparvovec an AAV Vector-Mediated Gene Transfer of hFVIII at a Dose of 4x1013 vg/kg in Hemophilia A Patients With Residual FVIII Levels ≤1IU/dL Receiving Prophylactic FVIII Infusions (GENEr8-2) (NCT03392974). | Phase 3: closed to recruitment due to lack of interest in the low-vector dose. LTFU continues. | ||
| BMN 270-303: A Phase 3b, Single Arm, Open-Label Study to Evaluate the Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII, With Prophylactic Corticosteroids in Hemophilia A Patients (GENEr8-3) (NCT04323098) | Enrolling subjects; no data reported. | ||
| UCL/AAV8 FVIII V3 peptide instead of B-domain | Gene Therapy for Haemophilia A (GO-8, NCT03001830) | 4 doses under evaluation: 6e11, 2e12, 4e12, or 6e12 vg/kg. Longest follow-up in 2e12-vg/kg dose cohort shows stable expression of FVIII out to 3 years at 15 IU/dL. | Open |
| Spark/Roche (SPK-8011) AAV-LK03-FVIII-SQ | SPK-8011-101: Gene Transfer, Dose-Finding Safety, Tolerability, and Efficacy Study of SPK-8011 (a Recombinant Adeno-Associated Viral Vector With Human Factor VIII Gene) in Individuals With Hemophilia A (NCT03003533) Together With Long-Term Follow-up Study (NCT03432520) | 4 cohorts (N = 18) over 5e11 to 2e12 vg/kg; mean FVIII expression ~12.9% ± 6.9% (1-stage clotting assay); 2 participants lost all expression because of transaminitis refractory to immunosuppression; 91% reduction in ABR; FVIII concentrate usage down by 96.4% | Closed to recruitment. LTFU continues. |
| Spark/Roche (SPK-8016) AAV-FVIII-SQ using a novel capsid | SPK-8016-101: Dose-Finding Study of SPK-8016 Gene Therapy in Patients With Hemophilia A to Support Evaluation in Individuals With FVIII Inhibitors (NCT03734588) | Recruitment closed. No data reported. | |
| Pfizer/Sangamo Bioscience (SB-525; giroctocogene fitelparvovec) AAV6 FVIII-SQ | SB-525-1603: A Phase 1/2, Open-Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 (PF-07055480) (Recombinant AAV2/6 Human Factor 8 Gene Therapy) in Adult Subjects With Severe Hemophilia A (Alta Study) (NCT03061201) | 4 cohorts (9e11, 2e12, 1e13, and 3e13 vg/kg; N = 11). Mean FVIII activity: ~43% and 25.7% at years 1 and 2, respectively @ 3e13-vg/kg dose level (N = 5); chromogenic assay. Transaminitis was detected in 5 of the 11 participants. | Closed to recruitment. LTFU continues. |
| C0371004: Phase III. An Open-Label, Non-investigational Product, Lead-in Study to Evaluate at Least 6 Months of Prospective Efficacy and Safety Data of Factor Replacement Therapy in the Usual Care Setting of Moderately Severe to Severe Adult Hemophilia B Subjects (FIX:C ≤2%) Who Are Negative for Nab to AAV Vector-Spark100 and Moderately Severe to Severe Hemophilia A Adult Subjects (FVIII:C ≤1%) Who Are Negative for Nab to AAV Vector Sb-525 Capsid (AAV6), Prior to the Respective Therapeutic Ph 3 Gene Therapy Studies (NAB Protocol) (NCT03587116) | Recruiting 250 subjects in this 6-month lead-in study to support the phase 3 intervention study. | ||
| C3731003: Phase 3, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of PF-07055480 (Recombinant AAV2/6 Human Factor VIII Gene Therapy) in Adult Male Participants With Moderately Severe to Severe Hemophilia A (FVIII:C ≤1%) (AFFINE) (NCT04370054) | Recruitment target = 60 patients. Phase 3 restarted following temporary regulatory hold for high FVIII levels (>150%) in some participants. | ||
| Bayer/Ultragenyx Therapeutics BAY 2599023 (DTX-201) AAVhu37 capsid pseudotyped FVIII-SQ | A Phase 1/2 Open-Label Safety and Dose-Finding Study of BAY2599023 (DTX201), an Adeno-Associated Virus (AAV) hu37-Mediated Gene Transfer of B-Domain Deleted Human Factor VIII, in Adults With Severe Hemophilia A (NCT03588299) | 9 participants enrolled sequentially into 1 of 3 dose cohorts (0.5e13, 1e13, and 2e13 vg/kg). FVIII expression levels for up to >23 months. Transaminitis observed in 5/9 participants. | |
| Takeda (TAK 754) AAV8-FVIII-SQ | A Study of BAX 888 in Male Adults With Severe Hemophilia A (NCT03370172) | 2e12- and 6e12-vg/kg dose cohorts assessed. Study suspended following transaminitis-mediated loss of FVIII expression in all participants. | |
ABR, annualized bleed rates; EU, European Union; LTFU, long-term follow-up.