A Study of Recombinant AAV2/6 Human Factor 8 Gene Therapy SB-525 (PF-07055480) in Subjects With Severe Hemophilia A

Phase 2

Completed

Conditions: Hemophilia A

Interventions: Biological: SB-525 (PF-07055480)

Registration Number: NCT03061201

Lead Sponsor: Pfizer

Brief Summary: The purpose of the study is to evaluate the safety, tolerability and time-course profile of FVIII activity after dosing with SB-525 (PF-07055480)

Detailed Description: The proposed clinical study uses a recombinant adeno-associated virus 2/6 (AAV2/6) vector encoding the cDNA for the B-domain deleted human F8 (hF8). The secreted FVIII has the same amino acid sequence as approved recombinant anti hemophilic factors (Refacto® and Xyntha®). The SB-525 (PF-07055480) vector encodes a liver-specific promotor module and AAV2/6 exhibits liver tropism, thus providing the potential for long-term hepatic production of FVIII in hemophilia A subjects.

The constant production of FVIII after a single SB-525 (PF-07055480) administration may provide potential benefit in durable protection against bleeding and the complications thereof without lifelong repetitive IV factor replacement administration.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 13

Inclusion Criteria

Male ≥18 years of age
Severe hemophilia A (past evidence of circulating FVIII activity of < 1% normal)
Treated or exposed to FVIII concentrates or cryoprecipitate for at least 150 exposure days
≥12 bleeding episodes if receiving on-demand therapy over the preceding 12 months
Agree to use double barrier contraceptive until at least 3 consecutive semen samples are negative for AAV 2/6 after SB-525 infusion

Exclusion Criteria

Presence of neutralizing antibodies
Current inhibitor, or history of FVIII inhibitor (except for transient low titer inhibitor detected in childhood)
History of hypersensitivity response to FVIII
History of Hepatitis B or HIV-1/2 infection
History of Hepatitis C, unless viral assays in two samples, collected at least 6 months apart, are negative
Evidence of any bleeding disorder in addition to hemophilia A
Markers of hepatic inflammation or overt or occult cirrhosis
History of chronic renal disease or creatinine ≥ 1.5 mg/dL
Presence of liver mass on magnetic resonance imaging (MRI), or, positive alpha fetoprotein
Presence of > grade 2 liver fibrosis on elastography for subjects with history of treated Hepatitis C or suspicion of chronic liver disease

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Sequential dose escalation	SB-525 (PF-07055480)	SB-525 (PF-07055480) is administered as a single infusion

Primary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	From Baseline (1 week prior to infusion) up to 5 years post-infusion (approximately 5 Years)	An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study intervention. An SAE was defined as any untoward medical occurrence that, at any dose, met one or more of the criteria as follows: death, life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly/birth defect and other situations per protocol. AEs included both SAEs and all non-SAEs.
Central FVIII Activity Levels by Chromogenic Assay at Year 1 (Week 52)	At Year 1 (Week 52)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by Chromogenic Assay at Year 2 (Week 104)	At Year 2 (Week 104)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by Chromogenic Assay at Year 3 (Week 156)	At Year 3 (Week 156)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by Chromogenic Assay at Year 4 (Week 208)	At Year 4 (Week 208)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by Chromogenic Assay at Year 5 (Week 260)	At Year 5 (Week 260)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by chromogenic assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 1 (Week 52)	At Year 1 (Week 52)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 2 (Week 104)	At Year 2 (Week 104)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 3 (Week 156)	At Year 3 (Week 156)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 4 (Week 208)	At Year 4 (Week 208)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Central FVIII Activity Levels by One-Stage Clotting Assay at Year 5 (Week 260)	At Year 5 (Week 260)	FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory. In this outcome measure results by one-stage clotting assay are reported.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 1 (Week 9 Through Week 53)	Year 1 (Week 9 through Week 53)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 1 included assessments from Week 9 through Week 53). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 2 (Week 54 Through Week 108)	Year 2 (Week 54 through Week 108)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 2 included assessments from Week 54 through Week 108). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 3 (Week 109 Through Week 160)	Year 3 (Week 109 through Week 160)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 3 included assessments from Week 109 through Week 160). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 4 (Week 161 Through Week 212)	Year 4 (Week 161 through Week 212)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 4 included assessments from Week 161 through Week 212). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by Chromogenic Assay at Yearly Interval 5 (Week 213 Through Week 264)	Year 5 (Week 213 through Week 264)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by chromogenic assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 5 included assessments from Week 213 through Week 264). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 1 (Week 9 Through Week 53)	Year 1 (Week 9 through Week 53)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 1 included assessments from Week 9 through Week 53). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 2 (Week 54 Through Week 108)	Year 2 (Week 54 through Week 108)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 2 included assessments from Week 54 through Week 108). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 3 (Week 109 Through Week 160)	Year 3 (Week 109 through Week 160)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 3 included assessments from Week 109 through Week 160). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 4 (Week 161 Through Week 212)	Year 4 (Week 161 through Week 212)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 4 included assessments from Week 161 through Week 212). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.
Geometric Mean of Central FVIII Activity Levels for Cohort 4 by One-Stage Clotting Assay at Yearly Interval 5 (Week 213 Through Week 264)	Year 5 (Week 213 through Week 264)	FVIII activity levels were analyzed in the central laboratory using chromogenic and one-stage clotting assay. In this outcome measure FVIII activity levels were assessed by one-stage clotting assay. As pre-specified, for each participant geometric mean of central FVIII activity levels was calculated of all eligible FVIII activity measurements for each yearly interval (for this outcome measure: Yearly Interval 5 included assessments from Week 213 through Week 264). Following this mean and standard deviation as summary statistics across all evaluable participants was calculated and is reported as data for this outcome measure.

Secondary Outcome Measures

Name	Time	Method
Total Annualized Bleeding Rate (ABR)	Pre-screening period: 12 months prior to screening; Post-infusion period: 3 weeks post-infusion up to date of day before start of prophylaxis or date of data cut or conclusion date, whichever was earlier (maximum up to 5 years)	Total ABR included both treated and untreated bleeding episodes. In this outcome measure total ABR for pre-screening and post-infusion are reported. Pre-screening total ABR was based on the total number of reported bleeding episodes during 12 months prior to screening visit as reported on CRF's Hemophilia A History page. Screening was 2 months before baseline. Post- infusion total ABR = number of all bleeding episodes starting 3 weeks after investigational product/ PF-07055480 (IP) infusion up to date of day before start of prophylaxis (or date of data cut or conclusion date)/ observation period in years, where observation period in years = date of day before start of prophylaxis or date of data cut or conclusion date - 3 weeks after date of IP infusion + 1)/365.25. For a participant who did not start prophylaxis the data cut date or conclusion date is used.
Total ABR by Severity	Post-infusion period: 3 weeks post-infusion up to date of day before start of prophylaxis or date of data cut or conclusion date, whichever was earlier (maximum up to 5 years)	Total ABR include both treated and untreated bleeding episodes. In this outcome measure total ABR by severity for post-infusion period is reported. Severity was categorized as mild, moderate and severe. Post- infusion total ABR = number of all bleeding episodes starting 3 weeks after IP infusion up to date of day before start of prophylaxis (or date of data cut or conclusion date)/ observation period in years, where observation period in years = date of day before start of prophylaxis or date of data cut or conclusion date - 3 weeks after date of IP infusion + 1)/365.25. For a participant who did not start prophylaxis the data cut date or conclusion date is used.
Annualized Infusion Rate (AIR)	Pre-infusion period: 30 days before screening up to pre-infusion (approximately up to 3.23 months); post-infusion period: 3 weeks post-infusion up to up to date of data cut or conclusion date (maximum up to 5 years)	AIR was calculated and reported for pre-infusion and post-infusion. AIR for pre-infusion was calculated as, a) Excluding prophylaxis: number of FVIII replacement infusions for reasons other than prophylaxis prior to IP infusion/ (\[date of IP infusion - date of screening\] + 30)\] \365.25, or b) number of FVIII replacement infusions for any reason prior to IP infusion/ (\[date of IP infusion - date of screening\] + 30)\] \365.25. Screening was 2 months before baseline and baseline was approximately 1-week prior to IP infusion. AIR for post- infusion was calculated as: number of FVIII replacement infusions started at 3 weeks after IP infusion up to date of data cut or conclusion date/ number of days in the observation period for the participant in years, where observation period in years = date of data cut or conclusion date - 3 weeks after date of IP infusion + 1)/365.25.
Change From Baseline in the EuroQol, 5 Dimensions, 5 Levels (EQ-5D-5L) Index Score at Weeks 12, 24 and 52; Months 24, 36, 48 and 60	Baseline; Weeks 12, 24, and 52; Months 24, 36, 48, and 60	EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group. It measures 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) of health on a 5-point scale. Each dimension had 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. EQ-5D-5L had 2 components: Index score and visual analogue scale (VAS). Index score was obtained, according to the health state defined by the 5 dimensions scores, from the Crosswalk Index value calculator and table lookup document under the target country population. A health state is defined by the combination of one level from each of the 5 dimensions. For this study, weights under the US population were used to obtain the Index score. Index score ranged between 0-1, where higher score indicates a better health state, and lower score indicate worse health state. Baseline was defined as the latest non-missing value before IP infusion.
Change From Baseline in the EQ-5D-5L- VAS Score at Week 12, 24, 52 and Month 24, 36, 48, 60	Baseline; Weeks 12, 24, and 52; Months 24, 36, 48, and 60	EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group. It measures 5 dimensions of health on a 5-point scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension is assessed with 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. EQ-5D-5L had 2 components: Index score and VAS. EQ-5D-5L VAS: Participants were asked to indicate their current health status on a scale of 0 (worst health) to 100 (best imaginable health), higher scores signified better health status. Baseline was defined as the latest non-missing value before IP infusion.
Number of Participants With Positive FVIII Inhibitor Levels During the Study	Baseline (one week prior to IP infusion) up to 5 years post-infusion	Positive FVIII inhibitor was assessed using central laboratory using Nijmegen method of the Bethesda assay in an individual with no prior history of FVIII inhibitor. Inhibitor assay results \>0.6 Bethesda units (BU) were considered as positive. Positive results at any timepoint were considered, even if subsequent inhibitor assessment was negative.
Peak Value of AAV2/6 (Adeno-associated Vector 2/6) Deoxyribonucleic Acid (DNA) in Plasma, Saliva, Semen, Stool and Urine	All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion	Peak (maximum) AAV2/6 vector DNA concentration (vg/mL) in plasma, saliva, semen, stool and urine were analyzed with quantitative real-time polymerase chain reaction (PCR). Participants must achieve 3 consecutive negative results for analysis for each sample.
Time to Peak Value of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine	All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion	Time to peak (maximum) AAV2/6 vector DNA concentration (vg/mL) in plasma, saliva, urine, stool and semen were analyzed with quantitative real-time PCR. Participants must achieve 3 consecutive negative results for analysis for each sample; where negative suggests values under the limit of detection.
Time to Undetectable (Negative) Value of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine	All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion	Time to undetectable (negative) value of AAV2/6 vector DNA concentration (vg/mL) in plasma, saliva, urine, stool and semen were analyzed with quantitative real-time PCR. Time to undetectable is defined as the number of days from IP infusion until the first of 3 consecutive specimens under the limit of detection (negative).
Time to Last of 3 Consecutive Negative Values of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine	All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion	Time to last of 3 consecutive negative value of AAV2/6 vector DNA concentration (vg/mL) in plasma, saliva, urine, stool and semen were analyzed with quantitative real-time PCR.
Time to Last Positive Value Prior to First of 3 Consecutive Negatives of AAV2/6 Vector DNA in Plasma, Saliva, Semen, Stool and Urine	All samples: Baseline, Day 7, Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 and every month after Week 52 until Month 60 until 3 consecutive negative samples are obtained on a sample-type basis; additional for plasma at 12 hours post-infusion	Time to last positive value prior to first of 3 consecutive negatives of AAV2/6 vector DNA concentration (vg/mL) in plasma, saliva, urine, stool and semen were analyzed with quantitative real-time PCR, where positive suggests values above the limit of detection.

Trial Locations

Locations (22): Arkansas Children's Hospital
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Little Rock, Arkansas, United States
City of Hope Medical Center
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Duarte, California, United States
Midtown Ambulatory Care Center
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Sacramento, California, United States
UC Davis Ambulatory Care Clinic
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Sacramento, California, United States
UC Davis Comprehensive Cancer Center
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Sacramento, California, United States
UC Davis CTSC Clinical Research Center
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Sacramento, California, United States
UC Davis Hemophilia Treatment Center
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Sacramento, California, United States
UC Davis Investigational Drug Services Pharmacy
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Sacramento, California, United States
UC Davis Medical Center
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Sacramento, California, United States
University of California, San Francisco - Investigational Drug Service (IDS) Pharmacy
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San Francisco, California, United States
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Arkansas Children's Hospital
🇺🇸Little Rock, Arkansas, United States