Adeno-Associated Virus (AAV), Blood Coagulation Disorder, Blood Coagulation Disorders, Inherited, Coagulation Protein Disorders, Factor VIII (FVIII), Factor VIII (FVIII) Deficiency, Factor VIII (FVIII) Gene, Factor VIII (FVIII) Protein, Gene Therapy, Genetic Diseases, Inborn, Genetic Diseases, X-Linked, Gene Transfer, Hematologic Diseases, Hemorrhagic Disorders, Inhibitors, Recombinant, Vector
Conditions
Brief summary
SPK-8016 is in development for the treatment of patients with inhibitors to FVIII. This Phase 1/2, open-label, non-randomized, dose-finding study to evaluate the safety, efficacy, and tolerability of SPK-8016 in adult males with severe hemophilia A and no measurable inhibitor against FVIII.
Interventions
GENETICSPK-8016
adeno-associated viral vector
Sponsors
Spark Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be male and ≥18 years of age; 2. Have clinically severe hemophilia A, defined as: 1. \<1% (\<1 IU/dL) endogenous FVIII activity levels as historically documented by a certified laboratory or screening data results; OR 2. 1-2% (1-2 IU/dL) endogenous FVIII activity levels and \> 10 bleeding events per year (in the last 52 weeks prior to screening); OR 3. 1-2% (1-2 IU/dL) endogenous FVIII activity levels and on prophylaxis; 3. Have had \>150 exposure days (EDs) to any recombinant and/or plasma-derived FVIII concentrates or cryoprecipitates 4. Have no prior history of hypersensitivity or anaphylaxis associated with any FVIII or IV immunoglobulin administration 5. Have no measurable inhibitor against FVIII as assessed by central laboratory, have no confirmed history of clinically significant FVIII inhibitor, and no clinical signs or symptoms of decreased response to FVIII administration (Note: family history of inhibitors will not exclude study participation) 6. Agree to use reliable barrier contraception after the administration of SPK-8016 until notified by the Investigator.
Exclusion criteria
1. Have active hepatitis B or C 2. Have significant underlying liver disease. 3. Have serological evidence of HIV-1 or HIV-2 with CD4 counts ≤200/mm3. Participants who are HIV-positive and stable, with an adequate CD4 count (\>200/mm3) and undetectable viral load, and are on an antiretroviral drug regimen are eligible to enroll 4. Have detectable antibodies reactive with AAV-Spark capsid 5. Have history of chronic infection or other chronic disease 6. Have been dosed in a previous gene therapy research trial within the last 52 weeks or with an investigational drug within the last 12 weeks 7. Any concurrent clinically significant major disease (such as liver abnormalities or type I diabetes) or other condition that, in the opinion of the Investigator and/or Sponsor, makes the subject unsuitable for participation in the study; 8. Unable or unwilling to comply with the schedule of visits and study assessments described in the clinical protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Infusion Rate | From 28 days post vector administration up to week 52 | — |
| Peak FVIII Activity Levels Assessed by Coagulation Clotting Assays | Up to week 52 | — |
| Steady-state FVIII Activity Levels Assessed by Coagulation Clotting Assays | Up to week 52 | — |
| Number of Bleeding Events (Spontaneous and Traumatic) Since 28 Day Post Vector Administration | From 28 days post vector administration up to week 52 | — |
| Number of Participants With Adverse Events (AEs) | Up to week 52 | An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. |
| Number of Participants With Hepatic Transaminase Elevation Requiring Immunosuppression. | Up to week 52 | — |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With Vector-shedding of SPK-8016 in Bodily Fluids | Up to week 52 |
| Number of Participants With Immune Responses to AAV Capsid Protein and BDD-hFVIII Transgene | Up to week 52 |
| Time to Achieve Steady-state FVIII Activity Levels | Up to week 52 |
Countries
United States
Participant flow
Pre-assignment details
A dose-finding part of this trial was planned but no participants were enrolled into the higher dose arms. All participants received SPK-8016 5x10\^11 vg/kg
Participants by arm
| Arm | Count |
|---|---|
| SPK-8016 Participants received a single intravenous infusion of SPK-8016 at 5x10\^11 vg/kg. | 4 |
| Total | 4 |
Baseline characteristics
| Characteristic | SPK-8016 |
|---|---|
| Age, Continuous | 36.3 years STANDARD_DEVIATION 19.29 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 4 / 4 |
| serious Total, serious adverse events | 2 / 4 |
Outcome results
Primary
Annualized Infusion Rate
Time frame: From 28 days post vector administration up to week 52
Population: The FAS included all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SPK-8016 | Annualized Infusion Rate | NA Annualized Infusion Rate |
Primary
Number of Bleeding Events (Spontaneous and Traumatic) Since 28 Day Post Vector Administration
Time frame: From 28 days post vector administration up to week 52
Population: The FAS included all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SPK-8016 | Number of Bleeding Events (Spontaneous and Traumatic) Since 28 Day Post Vector Administration | Traumatic | 6 Number of bleeding events |
| SPK-8016 | Number of Bleeding Events (Spontaneous and Traumatic) Since 28 Day Post Vector Administration | Spontaneous | 1 Number of bleeding events |
Primary
Number of Participants With Adverse Events (AEs)
An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time frame: Up to week 52
Population: The FAS included all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-8016 | Number of Participants With Adverse Events (AEs) | 4 Participants |
Primary
Number of Participants With Hepatic Transaminase Elevation Requiring Immunosuppression.
Time frame: Up to week 52
Population: The FAS included all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-8016 | Number of Participants With Hepatic Transaminase Elevation Requiring Immunosuppression. | 0 Participants |
Primary
Peak FVIII Activity Levels Assessed by Coagulation Clotting Assays
Time frame: Up to week 52
Population: The FAS included all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SPK-8016 | Peak FVIII Activity Levels Assessed by Coagulation Clotting Assays | NA percentage of normal activity |
Primary
Steady-state FVIII Activity Levels Assessed by Coagulation Clotting Assays
Time frame: Up to week 52
Population: The FAS included all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SPK-8016 | Steady-state FVIII Activity Levels Assessed by Coagulation Clotting Assays | NA percentage of normal activity |
Secondary
Number of Participants With Immune Responses to AAV Capsid Protein and BDD-hFVIII Transgene
Time frame: Up to week 52
Population: The FAS includes all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-8016 | Number of Participants With Immune Responses to AAV Capsid Protein and BDD-hFVIII Transgene | 3 Participants |
Secondary
Number of Participants With Vector-shedding of SPK-8016 in Bodily Fluids
Time frame: Up to week 52
Population: Results were uninterpretable due to a technical error.
Secondary
Time to Achieve Steady-state FVIII Activity Levels
Time frame: Up to week 52
Population: The FAS included all enrolled participants who received the infusion of SPK-8016.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| SPK-8016 | Time to Achieve Steady-state FVIII Activity Levels | NA hours |