Study to Evaluate the Efficacy and Safety of PF-07055480 / Giroctocogene Fitelparvovec Gene Therapy in Moderately Severe to Severe Hemophilia A Adults

FVIII activity level based on central laboratory chromogenic assay at Month 15

Treated bleed was defined as an event which necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. In this outcome measure treated ABR following infusion of PF-07055480 in current study (post-infusion) and on prior FVIII prophylaxis regimen prior to infusion of PF-07055480 (pre-infusion, data collected from lead-in study C0371004) were reported. Treated ABR for FVIII prophylaxis= [(Number of treated bleeding episodes during pre-infusion period)*365.25]/ [(Number of days of follow-up in pre-infusion period)]. Treated ABR for PF-07055480: [(Number of treated bleeding episodes during post-infusion period)*365.25] / [(last date of post-infusion period - date of PF-07055480 infusion) - 77 days + 1].

AIR: [(Number of exogenous FVIII product infusions for any purpose during the given time period) * 365.25]/ (Number of days of follow-up in the given time period). In this outcome measure AIR of exogenous FVIII activity in current study (post-infusion) and on prior FVIII prophylaxis regimen prior to infusion of PF-07055480 (pre-infusion, data collected from lead-in study C0371004) were reported.

FVIII activity levels were assessed using chromogenic assay and one-stage clotting assay analyzed in the central laboratory. As pre-specified, for each participant, a geometric mean laboratory reading for FVIII activity was used to derived one single FVIII level by including all assessments from Week 12 through 15 months following PF-07055480 infusion; then mean and standard deviation as summary statistics was calculated across all evaluable participants and reported as data for this outcome measure. This resulting Factor VIII activity is expressed as percent of normal (%); which is used interchangeable with international unit per deciliter (IU/dL). "Normal Range" is typically considered 50-150% (or 50-150 IU/dL).

Annualized FVIII consumption was reported in international units per kilogram (IU/kg) and total units (in IU). This outcome measure compared data collected from lead-in study C0371004 and from current study C3731003. Data is reported in this outcome measure as mean of annualized FVIII consumption from all participants in this analysis population.

Bleeds based on cause:spontaneous(bleeding for no apparent/known reason particularly into the joint,muscles and soft tissue)and traumatic(bleeding event occurring for an apparent/known reason).Bleeds related to a procedure/surgery such as hematomas/bruising which resulted from any surgeries or invasive procedure,or invasive diagnostic procedures were not counted as bleeds.Treated:necessitated administration of coagulation factor within 72hrs of sign or symptom of bleeding. Untreated:did not necessitate administration of coagulation factor within 72hrs of sign and symptom of bleeding.ABR for FVIII prophylaxis=[(Number of total bleeding episodes during pre-infusion)*365.25]/(Number of days of follow-up in pre-infusion period).ABR for PF-07055480[(Number of total bleeding episodes during post-infusion period)*365.25]/[(last date of post-infusion period-date of PF-07055480 infusion)-77 days+1].This outcome measure compared data collected from lead-inC0371004and from current studyC3731003.

Bleeds based on cause were spontaneous (bleeding for no apparent/known reason particularly into the joint, muscles and soft tissues) and traumatic (bleeding event occurring for an apparent/known reason). Bleeds related to a procedure/surgery such as hematomas/bruising which resulted from any surgeries or invasive procedures, or invasive diagnostic procedure were not counted as bleeds. Treated: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Treated ABR for FVIII prophylaxis= [(Number of treated bleeding episodes during pre-infusion period)*365.25]/ (Number of days of follow-up in pre-infusion period). Treated ABR for PF-07055480: [(Number of treated bleeding episodes during post-infusion period)*365.25] /[(last date of post-infusion period - date of PF-07055480 infusion) - 77 days + 1]. This outcome measure compared data collected from lead-in study C0371004 and from current study C3731003.

Target joint:major joint(hip,elbow,wrist,shoulder,knee\&ankle)with repeated bleed(3 or more spontaneous bleed into a single joint within6month).Joint bleed:bleeding episode by rapid loss of motion as compared with baseline,associated with pain or unusual sensation,swelling\&warmth over the joint.Muscle:bleeding episode into a muscle,determined by imaging study,associated with pain\&or swelling \&functional impairment.Treated:necessitated administration of coagulation factor within72hrs of sign or symptom of bleeding.Untreated:did not necessitate administration of coagulation factor within72hrs of sign\&symptom of bleeding.FVIII prophylaxis=[(Number of total bleeding episodes during pre-infusion)*365.25]/(Number of days of follow-up in pre-infusion).PF-07055480:[(Number of total bleeding episodes during post-infusion)*365.25]/[(last date of post infusion-date of PF-07055480 infusion)-77days+1].This outcome measure compared data collected from lead-inC0371004 and from current studyC3731003.

Target joint:major joint(hip,elbow,wrist,shoulder,knee,and ankle)with repeated bleeds(3 or more spontaneous bleeds into a single joint within 6month).Joint bleed:bleeding episode characterized by rapid loss of range of motion as compared with baseline,associated with pain or an unusual sensation in the joint,palpable swelling,and warmth of the skin over the joint.Muscle:bleeding episode into a muscle,determined clinically and/or by imaging study,associated with pain and/or swelling and functional impairment.Treated:necessitated administration of coagulation factor within72 hrs of sign or symptom of bleeding.FVIII prophylaxis=[(Number of treated bleeding episodes during pre-infusion)*365.25]/(Number of days of follow-up in pre-infusion).PF-07055480:[(Number of treated bleeding episodes during post-infusion)*365.25]/[(last date of post-infusion-date of PF-07055480 infusion)-77days+1].This outcome measure compared data collected from lead-in studyC0371004 and from current studyC3731003.

Bleeds for evaluation included both treated and untreated bleeds. Treated bleed: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Untreated bleed: did not necessitate administration of coagulation factor within 72 hours of signs and symptoms of bleeding. In this outcome measure percentage of participants without bleeds following infusion of PF-07055480 in current study (post-infusion) and on prior FVIII prophylaxis regimen prior to infusion of PF-07055480 (pre-infusion) were reported. This outcome measure compared data collected from lead-in study C0371004 and from current study C3731003.

FVIII activity levels were assessed using chromogenic and one-stage clotting assay and which were analyzed in the central laboratory.

A qualified healthcare professional assessed six joints (left ankle, right ankle, left elbow, right elbow, left knee, right knee) scored from 0 to 20 based on: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength. Gait was scored (0 to 4) based on walking, stairs, running, hopping on one leg. Total HJHS score = sum of scores from all six joints (left ankle, right ankle, left elbow, right elbow, left knee, right knee) + gait score, ranged from 0 to 124, with the higher score indicated the number equating to more severe joint damage.

Haem-A-QoL assessed health-related quality of life in adult participants with hemophilia. It contains 46 items with 10 domains that assesses health in the following areas: physical health; feelings; view of self; sports and leisure; work and school; dealing with Haemophilia; treatment; future; family planning; and partnership and sexuality. All items are based on 5-point Likert type scale (1= never, 2= rarely, 3= sometimes, 4= often, 5= all the time). Scoring is performed by averaging non-missing item responses for each domain, then rescaled to be on 0 to 100, with lower scores representing higher quality of life. Total score= was averaged across the 46 items values and then rescaled on 0 to 100, with lower scores representing better quality of life and physical health status. Change from baseline in physical Health domain score was reported in this outcome measure.

The HAL was a multiple domain measure of the impact of hemophilia on functional abilities in adults. The 7 domains of this instrument contained 42 items in total, as follows:lying/sitting/kneeling/standing; lower (leg) functioning; upper (arm) functioning; transportation; self-care; household tasks; and sports/leisure. Items were rated on 6-point scale 1 (impossible) to 6 (never) that described difficulty due to hemophilia. HAL total score was calculated according to the Van Genderen scoring algorithm, had a transformed score range from 0 to 100; higher scores indicate better quality of life, that is, less functional limitations in performing tasks. Change from baseline in complex lower extremity activities component score was reported in this outcome measure.

Treated ABR: An event necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding (protocol definition, unless specifically referring to untreated bleed). Untreated ABR: A bleeding event not necessitating administration of coagulation factor within 72 hours of signs and symptoms of bleeding.

FVIII activity levels will be assessed using one stage assay and chromogenic assay in the central lab.

AIR: [(Number of exogenous FVIII product infusions for any purpose during the given time period)* 365.25]/ (Number of days of follow-up in the given time period).

Annualized FVIII consumption will be reported in IU/kg and total units (in IU).

Bleeds based on cause were spontaneous (bleeding for no apparent/known reason particularly into the joint, muscles and soft tissue) and traumatic (bleeding event occurring for an apparent/known reason). Bleeds related to a procedure/surgery such as hematomas/bruising which resulted from any surgeries or invasive procedures, or invasive diagnostic were not counted as bleeds. Treated: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Untreated: did not necessitate administration of coagulation factor within 72 hours of signs and symptoms of bleeding.

Bleeds based on cause were spontaneous (bleeding for no apparent/known reason particularly into the joint, muscles and soft tissue) and traumatic (bleeding event occurring for an apparent/known reason). Bleeds related to a procedure/surgery such as hematomas/bruising which resulted from any surgeries or invasive procedures, or invasive diagnostic were not counted as bleeds. Treated bleed: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding.

Target joint: major joint (hip, elbow, wrist, shoulder, knee, and ankle) with repeated bleeds (3 or more spontaneous bleed into a single joint within 6 month). Joint bleed: bleeding episode by rapid loss of range of motion compared with baseline, associated with pain or an unusual sensation in the joint, swelling. Muscle bleed: bleeding episode into a muscle, determined by imaging study, associated with pain and/or swelling and functional impairment. Treated bleed: necessitated administration of coagulation factor within 72 hrs of sign or symptom of bleeding. Untreated bleed: did not necessitate administration of coagulation factor within 72 hrs of sign and symptom of bleeding.

Target joint: major joint (hip, elbow, wrist, shoulder, knee, and ankle) with repeated bleeds (3 or more spontaneous bleed into a single joint within 6 month). Joint bleed: bleeding episode by rapid loss of range of motion compared with baseline, associated with pain or an unusual sensation in the joint, swelling. Muscle bleed: bleeding episode into a muscle, determined by imaging study, associated with pain and/or swelling and functional impairment. Treated bleed: necessitated administration of coagulation factor within 72 hrs of sign or symptom of bleeding.

Bleeds for evaluation included both treated and untreated bleeds. Treated bleed: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Untreated bleed: did not necessitate administration of coagulation factor within 72 hours of signs and symptoms of bleeding.

Treated bleed: bleeding event necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding.

Bleeds for evaluation included both treated and untreated bleeds. Treated bleed: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Untreated bleed: did not necessitate administration of coagulation factor within 72 hours of signs and symptoms of bleeding.

A qualified healthcare professional assessed six joints (left ankle, right ankle, left elbow, right elbow, left knee, right knee) scored from 0 to 20 based on: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength. Gait was scored (0 to 4) based on walking, stairs, running, hopping on one leg. Total score = sum of scores from all joints + gait score, ranged from 0 to 124, with the higher score indicated the number equating to more severe joint damage.

Haem-A-QoL assessed health-related quality of life in adult participants with hemophilia. It contains 46 items with 10 domains that assesses health in the following areas: physical health; feelings; view of self; sports and leisure; work and school; dealing with Haemophilia; treatment; future; family planning; and partnership and sexuality. All items are based on 5-point Likert type scale (1= never, 2= rarely, 3= sometimes, 4= often, 5= all the time). Scoring is performed by averaging non-missing item responses for each domain, then rescaled to be on 0 to 100, with lower scores representing higher quality of life. Total score= was averaged across the 46 items values and then rescaled on 0 to 100, with lower scores representing better quality of life and physical health status. Change from baseline in physical Health domain score will be reported in this outcome measure.

The HAL was a multiple domain measure of the impact of hemophilia on functional abilities in adults. The 7 domains of this instrument contained 42 items in total, as follows:lying/sitting/kneeling/standing; lower (leg) functioning; upper (arm) functioning; transportation; self-care; household tasks; and sports/leisure. Items were rated on 6-point scale 1 (impossible) to 6 (never) that described difficulty due to hemophilia. HAL total score was calculated according to the Van Genderen scoring algorithm, had a transformed score range from 0 to 100; higher scores indicate better quality of life, that is, less functional limitations in performing tasks. Change from baseline in complex lower extremity activities component score will be reported in this outcome measure.

Treated ABR: an event necessitating administration of coagulation factor within 72 hours of signs or symptoms of bleeding.

Bleeds based on cause were spontaneous (bleeding for no apparent/known reason particularly into the joint, muscles and soft tissue) and traumatic (bleeding event occurring for an apparent/known reason). Bleeds related to a procedure/surgery such as hematomas/bruising which resulted from any surgeries or invasive procedures, or invasive diagnostic were not counted as bleeds. Treated bleed: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding.

Target joint based on location: major joint (hip, elbow, wrist, shoulder, knee, and ankle) with repeated bleeds (3 or more spontaneous bleeds into a single joint within a consecutive 6-month period). Joint bleed: bleeding episode characterized by rapid loss of range of motion as compared with baseline, associated with pain or an unusual sensation in the joint, palpable swelling, and warmth of the skin over the joint. Muscle bleed: bleeding episode into a muscle, determined clinically and/or by imaging study, associated with pain and/or swelling and functional impairment. Treated bleed: necessitated administration of coagulation factor within 72 hrs of sign or symptom of bleeding.

AIR: [(Number of exogenous FVIII product infusions for any purpose during the given time period)* 365.25]/ (Number of days of follow-up in the given time period).

Annualized FVIII consumption will be reported in IU/kg and total units (in IU).

Bleeds based on cause were spontaneous (bleeding for no apparent/known reason particularly into the joint, muscles and soft tissue) and traumatic (bleeding event occurring for an apparent/known reason). Bleeds related to a procedure/surgery such as hematomas/bruising which resulted from any surgeries or invasive procedures, or invasive diagnostic were not counted as bleeds. Treated bleeds: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Untreated bleeds: did not necessitate administration of coagulation factor within 72 hours of signs and symptoms of bleeding.

Target joint: major joint (hip, elbow, wrist, shoulder, knee, and ankle) into which repeated bleeds occurred (3 or more spontaneous bleeds into a single joint within a consecutive 6month period). Target joint was considered resolved when there were =<2 bleed into the joint within a 12-month period. Joint bleed: A bleeding episode characterized by rapid loss of range of motion as compared with baseline that was associated with any combination of the following: pain or an unusual sensation in the joint, palpable swelling, and warmth of the skin over the joint. Muscle bleed: an episode of bleeding into a muscle, determined clinically and/or by imaging studies, generally associated with pain and/or swelling and functional impairment. Treated bleed: necessitated administration of coagulation factor within 72 hrs of sign or symptom of bleeding. Untreated bleed: did not necessitate administration of coagulation factor within 72 hrs of sign and symptom of bleeding.

Bleeds for evaluation included both treated and untreated bleeds. Treated bleed: necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Untreated bleed: did not necessitate administration of coagulation factor within 72 hours of signs and symptoms of bleeding.

Bleeds for evaluation included both treated and untreated bleeds. Treated bleed: bleeding event necessitated administration of coagulation factor within 72 hours of signs or symptoms of bleeding. Untreated bleed: bleeding event did not necessitate administration of coagulation factor within 72 hours of signs and symptoms of bleeding.

An AEs 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. Severe AEs: An event that prevented normal everyday activities. Severe was a category utilized for rating the intensity of an event, and both AEs and serious adverse events (SAEs) could be assessed as severe.

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. AESI included all medically important events that were reported as a serious adverse events (SAE), and any clinical reported thrombotic event or hypersensitivity/infusion-related reactions events assessed as non-serious AEs.

Number of participants with positive antibodies against AAV6 Capsid protein will be reported in this outcome measure.

The enzyme linked immune spot (ELISPOT) assay is a highly sensitive quantitative immunoassay for measuring relevant parameters of T cell activation (the frequency of cytokine-secreting cells at the single-cell level) on peripheral blood mononuclear cells (PBMC). T cell responses to AAV6 and FVIII will be evaluated at baseline and during study follow up, if corticosteroid treatment is needed for a suspected T-cell response.

Nijmegen Bethesda assay will be used to assess the presence of FVIII inhibitors (Inhibitory antibodies against FVIII that neutralize the clotting activity of FVIII). Positive refers to FVIII inhibitor levels by inhibitor assay results >=0.6 Bethesda units per milliliter (BU/mL).