Back to resultsA Gene Therapy Study for Hemophilia B
Primary Purpose
Hemophilia B
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
SPK-9001
Sponsored by
About this trial
This is an interventional treatment trial for Hemophilia B focused on measuring Hemophilia B, Blood Coagulation Disorders, Gene Therapy, Gene Transfer, Factor IX Deficiency, Factor IX Gene, Factor IX Protein, Vector, AAV
Eligibility Criteria
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
Sites / Locations
- UC Davis Comprehensive Cancer Center
- UC Davis CTSC Clinical Research Center
- UC Davis Ellison Ambulatory Care Clinic
- UC Davis Investigational Pharmacy
- UC Davis Medical Center
- University of Mississippi Medical Center
- Mississippi Center for Advanced Medicine
- Weill Cornell Medicine - New York Presbyterian Hospital
- The Children's Hospital of Philadelphia
- Royal Prince Alfred Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
SPK-9001
Arm Description
Single intravenous (i.v.) infusion of SPK-9001 [an adeno-associated viral (AAV) vector with human factor IX gene] Intervention: Gene Therapy / Gene Transfer
Outcomes
Primary Outcome Measures
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.
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.
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).
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.
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.
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.
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.
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).
Secondary Outcome Measures
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02484092
Brief Title
A Gene Therapy Study for Hemophilia B
Official Title
Gene Therapy, Open-label, Dose-escalation Study of PF-06838435 (SPK-9001) [Adeno-associated Viral Vector With Human Factor IX Gene] in Subjects With Hemophilia B
Study Type
Interventional
2. Study Status
Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
November 18, 2015 (Actual)
Primary Completion Date
April 8, 2019 (Actual)
Study Completion Date
April 8, 2019 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pfizer
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hemophilia B
Keywords
Hemophilia B, Blood Coagulation Disorders, Gene Therapy, Gene Transfer, Factor IX Deficiency, Factor IX Gene, Factor IX Protein, Vector, AAV
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
SPK-9001
Arm Type
Experimental
Arm Description
Single intravenous (i.v.) infusion of SPK-9001 [an adeno-associated viral (AAV) vector with human factor IX gene] Intervention: Gene Therapy / Gene Transfer
Intervention Type
Biological
Intervention Name(s)
SPK-9001
Intervention Description
A novel, bioengineered adeno-associated viral vector carrying human factor IX variant
Primary Outcome Measure Information:
Title
Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
Description
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
Title
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Description
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
Title
Number of Participants With Clinical Laboratory Abnormalities Reported as TEAE
Description
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
Title
Number of Participants With Drug -Related TEAEs and Serious Adverse Events (SAEs)
Description
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
Title
Number of Participants With Positive Immune Reponses Against Adeno-associated Virus Vector (AAV) Capsid
Description
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
Title
Number of Participants Who Reached > 150% Vector-derived FIX:C Activity Level After SPK-9001 Infusion
Description
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
Title
Number of Participants With FIX Inhibitor
Description
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
Title
Incremental Recovery of FIX Product
Description
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
Secondary Outcome Measure Information:
Title
FIX:C Activity
Description
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
Title
Change From Baseline in FIX:C Antigen Level at Steady State
Description
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
10. Eligibility
Sex
Male
Gender Based
Yes
Gender Eligibility Description
Genetic Males
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Pfizer CT.gov Call Center
Organizational Affiliation
Pfizer
Official's Role
Study Director
Facility Information:
Facility Name
UC Davis Comprehensive Cancer Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
UC Davis CTSC Clinical Research Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
UC Davis Ellison Ambulatory Care Clinic
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
UC Davis Investigational Pharmacy
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
UC Davis Medical Center
City
Sacramento
State/Province
California
ZIP/Postal Code
95817
Country
United States
Facility Name
University of Mississippi Medical Center
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216
Country
United States
Facility Name
Mississippi Center for Advanced Medicine
City
Madison
State/Province
Mississippi
ZIP/Postal Code
39110
Country
United States
Facility Name
Weill Cornell Medicine - New York Presbyterian Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Royal Prince Alfred Hospital
City
Camperdown/Sydney
State/Province
New South Wales
ZIP/Postal Code
2050
Country
Australia
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
IPD Sharing URL
https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Citations:
PubMed Identifier
29211678
Citation
George LA, Sullivan SK, Giermasz A, Rasko JEJ, Samelson-Jones BJ, Ducore J, Cuker A, Sullivan LM, Majumdar S, Teitel J, McGuinn CE, Ragni MV, Luk AY, Hui D, Wright JF, Chen Y, Liu Y, Wachtel K, Winters A, Tiefenbacher S, Arruda VR, van der Loo JCM, Zelenaia O, Takefman D, Carr ME, Couto LB, Anguela XM, High KA. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med. 2017 Dec 7;377(23):2215-2227. doi: 10.1056/NEJMoa1708538.
Results Reference
derived
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A Gene Therapy Study for Hemophilia B
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