Hemophilia B
Conditions
Keywords
Hemophilia B, Blood Coagulation Disorders, Gene Therapy, Gene Transfer, Factor IX Deficiency, Factor IX Gene, Factor IX Protein, Vector, AAV
Brief summary
A Phase 1/2, Open-Label, Non-Randomized, Dose-Escalation Study of SPK-9001 in Subjects with Hemophilia B.
Detailed description
Hemophilia B, or Christmas disease, is a genetic bleeding disorder resulting in the lack of ability to produce blood-clotting factor IX (FIX). Individuals with hemophilia B suffer repeated bleeding events, which can cause chronic joint disease and sometimes leads to death due to the inability for blood to clot efficiently. This chronic joint disease can have significant physical, psychosocial, and quality-of-life effects, including financial burden. The current treatment is intravenous infusion of FIX protein products, either prophylactically or in response to bleeding. The approach being tested in this study uses a novel recombinant adeno-associated virus (AAV), which in nature causes no disease, to deliver the human factor IX (hFIX) gene to the liver cells where FIX is normally made. Recent data of a gene therapy study showed preliminary encouraging results with the approach of using an AAV vector carrying the factor IX gene. This study will seek to determine the safety and kinetics of a single IV infusion of SPK-9001 (a novel AAV vector carrying a high specific activity factor IX variant).
Interventions
BIOLOGICALSPK-9001
A novel, bioengineered adeno-associated viral vector carrying human factor IX variant
Sponsors
Pfizer
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able to provide informed consent and comply with requirements of the study * Males ≥18 y.o. with confirmed diagnosis of hemophilia B (≤2 IU/dL or ≤2% endogenous factor IX) * Received ≥50 exposure days to factor IX products * A minimum average of 4 bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions * No measurable factor IX inhibitor as assessed by the central laboratory and have no prior history of inhibitors to factor IX protein * Agree to use reliable barrier contraception until 3 consecutive samples are negative for vector sequences
Exclusion criteria
* Evidence of active hepatitis B or C * Currently on antiviral therapy for hepatitis B or C * Have significant underlying liver disease * Have serological evidence\* of HIV-1 or HIV-2 with CD4 counts ≤200/mm3 (\* subjects who are HIV+ and stable with CD4 count \>200/mm3 and undetectable viral load are eligible to enroll) * Neutralizing antibodies reactive with AAV-Spark100 above and/or below a defined titre * Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational drug within the last 12 weeks * Unable or unwilling to comply with study assessments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incremental Recovery of FIX Product | Day 0 and Week 52 | Incremental recovery was determined as the peak factor level recorded within the first 3 hours after infusion and was reported as (IU/ml)/(IU/kg), using the formula:(\[Activity IU/mL peak post infusion\] - \[Activity IU/mL pre-infusion\]) / (IU/kg infused). |
| Number of Participants Who Reached > 150% Vector-derived FIX:C Activity Level After SPK-9001 Infusion | Baseline up to Week 52 | Based on non-clinical studies in non-human primates (NHPs), it was not predicted that vector-derived FIX:C activity levels \>150% of normal would be achieved in this study. However, thrombin antithrombin (TAT) levels as thrombotic potential were to be measured if vector derived FIX:C activity levels \>150% of normal were achieved in any participant during the study. Blood samples for TAT at Day 0 visit (prior to FIX protein product infusion) were used to establish baseline value. |
| Number of Participants With FIX Inhibitor | Baseline up to Week 52 | FIX inhibitors were measured using the Bethesda assay from the central and local laboratory. The Bethesda assay measures the amount of factor (FIX) inactivated when the plasma from the patient is incubated with an external source of factor for 2 hours at 37ºC. Inhibitor levels are quantified in Bethesda units (BU). An inhibitor titer of ≥ 0.6 BU/ml is to be taken as clinically significant. |
| Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings | Baseline up to Week 52 | Physical examination included examination of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision. |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Baseline up to Week 52 | Vital signs (temperature, respiratory rate, pulse rate, height, weight, systolic and diastolic blood pressure) were obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Clinical significance of vital signs was determined at the investigator's discretion. |
| Number of Participants With Clinical Laboratory Abnormalities Reported as TEAE | Baseline up to Week 52 | Following parameters were analyzed for laboratory examination: hematology (neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell \[RBC\] count, hemoglobin, hematocrit, platelet count); liver function (albumin, total bilirubin, total protein, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, GGT); Lipid panel (HDL, VLDL, triglycerides, total cholesterol); clinical chemistry (sodium, potassium, chloride, bicarbonate, glucose, phosphate, serum creatinine, BUN); urinalysis (specific gravity, pH, glucose, protein, blood, ketones; coagulation, immunology, etc. Investigators determined which laboratory abnormalities were reported as treatment-emergent adverse events (TEAEs). |
| Number of Participants With Drug -Related TEAEs and Serious Adverse Events (SAEs) | Baseline up to Week 52 | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. An AE was regarded as TEAE if the start date was on or after the infusion of SPK-9001 but before participant's last visit on study (or the date of withdrawal/the date of being lost to follow-up). Severe TEAEs were TEAEs that interfered significantly with participants' usual function. Treatment-related TEAEs were determined by the investigator. |
| Number of Participants With Positive Immune Reponses Against Adeno-associated Virus Vector (AAV) Capsid | Baseline up to Week 52 | Peripheral blood mononuclear cells (PBMC) results by interferon gamma enzyme-linked immunospot assay (ELISPOT) to assess cellular immune responses to AAV capsid and to FIX were presented. The ELISPOT is a type of assay that focuses on quantitatively measuring the frequency of cytokine secretion for a single cell. The positive ELISPOT results suggested a T-cell reaction to capsid protein. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FIX:C Antigen Level at Steady State | Week 12 up to Week 52 | The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity antigen levels were characterized by post-treatment population mean. |
| FIX:C Activity | Baseline up to Week 52 | All samples collected from participants for plasma FIX activity levels were analyzed and used to determine peak and steady-state vector-derived circulating FIX activity levels. The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity levels were characterized by post-treatment population mean. Dose escalation and dose level expansion strategies were employed in the study based on vector-derived FIX activity levels as well as any immune responses against AAV capsid. Steady-state levels were based on 2 separate vector-derived FIX:C activity level measurements (at least 2 weeks apart) starting from Week 8-12 with adequate washout. |
Countries
Australia, United States
Participant flow
Recruitment details
A total of 22 participants were screened, 15 participants were assigned to treatment and completed study. All 15 participants received the lowest dose in the study (5 x 10\^11 vg/kg). No participants were assigned to the 2 higher dose arms. Results presented here are from the lowest dose level.
Participants by arm
| Arm | Count |
|---|---|
| SPK-9001 (5 x 10^11 vg/kg) IV Infusion Participants were infused with 100 IU/kg of their usual FIX protein product over 10 minutes at Day 0 visit. Following the bolus infusion of the usual FIX protein product, the participant was infused with SPK-9001 (5 x 10\^11 vg/kg) for approximately 60 minutes via infusion pump. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | SPK-9001 (5 x 10^11 vg/kg) IV Infusion |
|---|---|
| Age, Continuous | 38.6 Years STANDARD_DEVIATION 14.5 |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants |
| Race/Ethnicity, Customized White or Caucasian | 12 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 15 |
| other Total, other adverse events | 14 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Incremental Recovery of FIX Product
Incremental recovery was determined as the peak factor level recorded within the first 3 hours after infusion and was reported as (IU/ml)/(IU/kg), using the formula:(\[Activity IU/mL peak post infusion\] - \[Activity IU/mL pre-infusion\]) / (IU/kg infused).
Time frame: Day 0 and Week 52
Population: Participants who had received 100 IU/kg of FIX protein product infusion and completed the blood sample collection within the first 3 hours post infusion for FIX protein product enabling determination of FIX incremental recovery.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Incremental Recovery of FIX Product | Day 0 | 0.0100 [IU/ml]/[IU/kg] | Standard Deviation 0.00242 |
| SPK-9001 (5 x 10^11 vg/kg) | Incremental Recovery of FIX Product | Week 52 | 0.0162 [IU/ml]/[IU/kg] | Standard Deviation 0.01351 |
Primary
Number of Participants Who Reached > 150% Vector-derived FIX:C Activity Level After SPK-9001 Infusion
Based on non-clinical studies in non-human primates (NHPs), it was not predicted that vector-derived FIX:C activity levels \>150% of normal would be achieved in this study. However, thrombin antithrombin (TAT) levels as thrombotic potential were to be measured if vector derived FIX:C activity levels \>150% of normal were achieved in any participant during the study. Blood samples for TAT at Day 0 visit (prior to FIX protein product infusion) were used to establish baseline value.
Time frame: Baseline up to Week 52
Population: All participants who received the infusion of SPK-9001.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants Who Reached > 150% Vector-derived FIX:C Activity Level After SPK-9001 Infusion | 0 Participants |
Primary
Number of Participants With Clinical Laboratory Abnormalities Reported as TEAE
Following parameters were analyzed for laboratory examination: hematology (neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell \[RBC\] count, hemoglobin, hematocrit, platelet count); liver function (albumin, total bilirubin, total protein, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, GGT); Lipid panel (HDL, VLDL, triglycerides, total cholesterol); clinical chemistry (sodium, potassium, chloride, bicarbonate, glucose, phosphate, serum creatinine, BUN); urinalysis (specific gravity, pH, glucose, protein, blood, ketones; coagulation, immunology, etc. Investigators determined which laboratory abnormalities were reported as treatment-emergent adverse events (TEAEs).
Time frame: Baseline up to Week 52
Population: All participants who received the infusion of SPK-9001.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants With Clinical Laboratory Abnormalities Reported as TEAE | 2 Participants |
Primary
Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
Physical examination included examination of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.
Time frame: Baseline up to Week 52
Population: All participants who received the infusion of SPK-9001.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings | 0 Participants |
Primary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital signs (temperature, respiratory rate, pulse rate, height, weight, systolic and diastolic blood pressure) were obtained with participant in the seated position, after having sat calmly for at least 5 minutes. Clinical significance of vital signs was determined at the investigator's discretion.
Time frame: Baseline up to Week 52
Population: All participants who received the infusion of SPK-9001.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 Participants |
Primary
Number of Participants With Drug -Related TEAEs and Serious Adverse Events (SAEs)
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. An AE was regarded as TEAE if the start date was on or after the infusion of SPK-9001 but before participant's last visit on study (or the date of withdrawal/the date of being lost to follow-up). Severe TEAEs were TEAEs that interfered significantly with participants' usual function. Treatment-related TEAEs were determined by the investigator.
Time frame: Baseline up to Week 52
Population: All participants who received the infusion of SPK-9001.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants With Drug -Related TEAEs and Serious Adverse Events (SAEs) | Drug-related TEAE | 2 Participants |
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants With Drug -Related TEAEs and Serious Adverse Events (SAEs) | Drug-related Serious TEAE | 0 Participants |
Primary
Number of Participants With FIX Inhibitor
FIX inhibitors were measured using the Bethesda assay from the central and local laboratory. The Bethesda assay measures the amount of factor (FIX) inactivated when the plasma from the patient is incubated with an external source of factor for 2 hours at 37ºC. Inhibitor levels are quantified in Bethesda units (BU). An inhibitor titer of ≥ 0.6 BU/ml is to be taken as clinically significant.
Time frame: Baseline up to Week 52
Population: All participants who received the infusion of SPK-9001.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants With FIX Inhibitor | 0 Participants |
Primary
Number of Participants With Positive Immune Reponses Against Adeno-associated Virus Vector (AAV) Capsid
Peripheral blood mononuclear cells (PBMC) results by interferon gamma enzyme-linked immunospot assay (ELISPOT) to assess cellular immune responses to AAV capsid and to FIX were presented. The ELISPOT is a type of assay that focuses on quantitatively measuring the frequency of cytokine secretion for a single cell. The positive ELISPOT results suggested a T-cell reaction to capsid protein.
Time frame: Baseline up to Week 52
Population: All participants who received the infusion of SPK-9001.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Number of Participants With Positive Immune Reponses Against Adeno-associated Virus Vector (AAV) Capsid | 2 Participants |
Secondary
Change From Baseline in FIX:C Antigen Level at Steady State
The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity antigen levels were characterized by post-treatment population mean.
Time frame: Week 12 up to Week 52
Population: Participants who had received SPK-9001 and had collected vector-derived FIX:C activity levels enabling acceptable determination of the peak and steady-state derived activity level.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 12 | -4.4 Percentage of Normal | Standard Deviation 19.26 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 14 | -4.7 Percentage of Normal | Standard Deviation 23.11 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 16 | -4.7 Percentage of Normal | Standard Deviation 19.79 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 18 | -5.8 Percentage of Normal | Standard Deviation 21.81 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 22 | -4.6 Percentage of Normal | Standard Deviation 22.06 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 26 | -6.6 Percentage of Normal | Standard Deviation 20.64 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 32 | -7.1 Percentage of Normal | Standard Deviation 20.48 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 42 | -4.9 Percentage of Normal | Standard Deviation 19.87 |
| SPK-9001 (5 x 10^11 vg/kg) | Change From Baseline in FIX:C Antigen Level at Steady State | Week 52 | -6.9 Percentage of Normal | Standard Deviation 19.7 |
Secondary
FIX:C Activity
All samples collected from participants for plasma FIX activity levels were analyzed and used to determine peak and steady-state vector-derived circulating FIX activity levels. The vector-derived endogenous (not affected by intercurrent FIX product infusions) FIX:C activity levels were characterized by post-treatment population mean. Dose escalation and dose level expansion strategies were employed in the study based on vector-derived FIX activity levels as well as any immune responses against AAV capsid. Steady-state levels were based on 2 separate vector-derived FIX:C activity level measurements (at least 2 weeks apart) starting from Week 8-12 with adequate washout.
Time frame: Baseline up to Week 52
Population: Participants who had received SPK-9001 and had collected vector-derived FIX:C activity levels enabling acceptable determination of the peak and steady-state derived activity level.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPK-9001 (5 x 10^11 vg/kg) | FIX:C Activity | Steady-State Level | 22.9 Percentage of Normal | Standard Deviation 9.89 |
| SPK-9001 (5 x 10^11 vg/kg) | FIX:C Activity | Peak Activity | 29.1 Percentage of Normal | Standard Deviation 11.63 |