Updated Follow-up of the Alta Study, a Phase 1/2, Open Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 Gene Therapy in Adult Patients with Severe Hemophilia A

Introduction: Hemophilia A is a rare blood disorder caused by an F8 variant resulting in insufficient Factor VIII (FVIII) activity. Updated results and follow-up of an ongoing gene therapy study in patients with severe hemophilia A are presented. Methods: The Alta study is a dose-ranging, single-dose study of SB-525 gene therapy, a recombinant adeno-associated virus (rAAV6) vector encoding an F8 gene. SB-525 was injected into 11 patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11, 2e12, 1e13 and 3e13 vg/kg) with expansion of the high dose cohort by 3 additional patients. Endpoints included: safety events, changes in circulating FVIII activity, FVIII antigen, FVIII usage, and frequency and severity of bleeding. Results: In the third cohort (1e13 vg/kg), a single infusion of SB-525 resulted in stable and clinically relevant increases in FVIII activity. Patients in the fourth cohort (high dose, 3e13 vg/kg) achieved FVIII levels within the normal range (Table 1), with no bleeding events reported up to 24 weeks post-injection. Patients treated at 3e13 vg/kg did not require FVIII replacement therapy following the initial prophylactic period of up to approximately 3 weeks post-SB-525 administration. No bleeding events were observed in any of the patients treated at the 3e13 vg/kg dose. One patient had a treatment-related serious adverse event of hypotension and fever, with symptoms of headache and tachycardia, which occurred ~6 hours after completion of the vector infusion and resolved with treatment within 24 hours. In the three first cohorts, no ALT elevation requiring more than 7 days of corticosteroid treatment was observed. Of the 5 patients treated to date in the high dose cohort, 3 followed for at least 8 weeks showed transient and mild (grade 1) ALT elevations. All responded to corticosteroids within one week. At the time of abstract submission, all patients were off corticosteroids. FVIII antigen was assessed by ELISA, and preliminary results from the high dose cohort showed a good correlation by chromogenic assay between the specific activity of SB-525 derived FVIII and Xyntha, a recombinant B-domain deleted protein control. Dosing in the fourth cohort is ongoing, and additional analyses of the trial data including FVIII levels, bleeding rate and factor usage will be presented as available. Four- to 11-month follow-up data on all patients in the fourth dose cohort will also be presented. Conclusions: To date, treatment with a single infusion of SB-525 gene therapy resulted in dose-dependent and sustained increases in FVIII levels, with a substantial decrease in FVIII usage, and no bleeding episodes recorded in the highest dose cohort. Patients treated in the highest dose cohort achieved FVIII activity in the normal range. No ALT elevations persisting longer than 7 days were observed in the first three dose cohorts. The study is ongoing, and the results support further development of SB-525 for the treatment of severe Hemophilia A. Disclosures Giermasz: uniQure: Consultancy, Other: Research; Sangamo: Other: Research; Bioverativ/Sanofi: Consultancy, Speakers Bureau; BioMarin: Consultancy, Other: Research; Genentech/Roche: Consultancy, Other: Research, Speakers Bureau. Arkin:Pfizer: Employment, Equity Ownership. Di Russo:Pfizer: Employment, Equity Ownership. Snyder:Sangamo Therapeutics: Employment. Woolfson:Sangamo Therapeutics: Employment, Equity Ownership. Rouy:Sangamo Therapeutics: Employment, Equity Ownership

Activity of transgene-produced B-domain–deleted factor VIII in human plasma following AAV5 gene therapy

Adeno-associated virus (AAV)-based gene therapies can restore endogenous factor VIII (FVIII) expression in hemophilia A (HA). AAV vectors typically use a B-domain–deleted FVIII transgene, such as human FVIII-SQ in valoctocogene roxaparvovec (AAV5-FVIII-SQ). Surprisingly, the activity of transgene-produced FVIII-SQ was between 1.3 and 2.0 times higher in one-stage clot (OS) assays than in chromogenic-substrate (CS) assays, whereas recombinant FVIII-SQ products had lower OS than CS activity. Transgene-produced and recombinant FVIII-SQ showed comparable specific activity (international units per milligram) in the CS assay, demonstrating that the diverging activities arise in the OS assay. Higher OS activity for transgene-produced FVIII-SQ was observed across various assay kits and clinical laboratories, suggesting that intrinsic molecular features are potential root causes. Further experiments in 2 participants showed that transgene-produced FVIII-SQ accelerated early factor Xa and thrombin formation, which may explain the higher OS activity based on a kinetic bias between OS and CS assay readout times. Despite the faster onset of coagulation, global thrombin levels were unaffected. A correlation with joint bleeds suggested that both OS and CS assay remained clinically meaningful to distinguish hemophilic from nonhemophilic FVIII activity levels. During clinical development, the CS activity was chosen as a surrogate end point to conservatively assess hemostatic efficacy and enable comparison with recombinant FVIII-SQ products. Relevant trials are registered on clinicaltrials.gov as #NCT02576795 and #NCT03370913 and, respectively, on EudraCT (European Union Drug Regulating Authorities Clinical Trials Database; https://eudract.ema.europa.eu) as #2014-003880-38 and #2017-003215-19

Updated Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (SB-525) Gene Therapy in Adults with Severe Hemophilia a

Introduction: Hemophilia A is a rare bleeding disorder caused by pathogenic variants in the F8 gene, resulting in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)-mediated gene transfer enables the delivery of a modified functional F8 gene to hepatocytes that subsequently synthesize FVIII at levels that may prevent bleeding events in the absence of exogenous FVIII. Updated results and follow-up from the Alta study, an ongoing gene therapy study in patients with severe hemophilia A, are presented. Methods: The Alta study is a phase 1/2 dose-ranging, single-dose study of giroctocogene fitelparvovec (also known as SB-525 and PF-07055480), a recombinant AAV serotype 6 (rAAV6) vector encoding a modified F8 gene. Adults aged ≥18 years with severe hemophilia A were eligible for inclusion. Giroctocogene fitelparvovec was infused into patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11, 2e12, 1e13, and 3e13 vg/kg). The 3e13 vg/kg dose cohort was expanded with 3 additional patients. Key end points included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. Presented data are from the ongoing Alta study (NCT#03061201; data cutoff date, 26 May 2020; database not locked; data reflect those at time of data cutoff, have not undergone standard quality checks, and may be subject to change). Results: Eleven male patients participated in the study (mean [SD] age, 30.3 [7.8] years; white, 81.8%). As of the cutoff date, patients have been followed for 35 to 144 weeks; one patient in the 1e13 vg/kg cohort discontinued from the study. Overall, the most commonly reported adverse events (AEs; n) included increased alanine aminotransferase (ALT; 8 [72.7%]), increased aspartate aminotransferase (AST; 5 [45.5%]), upper respiratory tract infection (4 [36.4%]), and pyrexia (4 [36.4%]). Treatment-related serious AEs were reported in 1 patient (in the 3e13 vg/kg cohort) who experienced hypotension and fever ≈6 hours after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge. In the 3 lower-dose cohorts, no ALT elevation requiring more than 7 days of corticosteroid treatment was observed. Of the 5 patients in the 3e13 vg/kg cohort, 4 had elevations in ALT that were managed with a tapering course of corticosteroids (ranging from 10-134 days) without loss of clinically relevant FVIII activity through 40 weeks, as evidenced by a lack of bleeding events before and after treatment with corticosteroids. Increases in FVIII activity from baseline were generally dose-dependent. Patients in the 3e13 vg/kg cohort achieved a mean normal-range of FVIII activity within 5 weeks post-infusion, with mean FVIII activity maintained through week 40, which is the last time point with data for all 5 patients in this cohort (Table). Following the initial prophylactic period of up to ≈3 weeks after giroctocogene fitelparvovec administration, no bleeding events occurred in any patient treated in the 3e13 vg/kg cohort. Use of FVIII replacement therapy ≥3 weeks after giroctocogene fitelparvovec administration was reported in 5/6 patients in the lower-dose cohorts (range: 9-115 infusions); none of the patients in the 3e13 vg/kg cohort required FVIII replacement beyond initial use of prophylactic factor for up to ≈3 weeks (prophylactic coverage stopped 3 weeks and 2 days after giroctocogene fitelparvovec administration in 1 patient in the 3e13 vg/kg cohort). Conclusions: To date, a single infusion of giroctocogene fitelparvovec gene therapy in patients with severe hemophilia A resulted in dose-dependent and sustained increases in FVIII levels without administration of exogenous FVIII, bleeding episodes or sustained adverse events in the highest-dose cohort (3e13 vg/kg). Additionally, patients treated in the highest-dose cohort achieved a mean FVIII activity in the normal range within 5 weeks, which was maintained through week 40. Data on all patients with more than 1 year of follow-up will also be presented. The study is ongoing, and these interim results support further development of giroctocogene fitelparvovec for the treatment of patients with severe hemophilia A. Disclosures Leavitt: BioMarin: Membership on an entity's Board of Directors or advisory committees. Konkle:Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Uniquire: Research Funding; CSL Behring: Consultancy; BioMarin: Consultancy; Baxalta: Research Funding; Spark: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sigilon: Consultancy, Research Funding; Roche: Consultancy. Stine:Biomarin: Consultancy; Applied Stem Cell Therapeutics: Consultancy. Visweshwar:Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Giermasz:uniQure: Consultancy, Research Funding; Sangamo Therapeutics: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau. Arkin:Pfizer: Current Employment, Current equity holder in publicly-traded company, Other: own stock/options in the company. Fang:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Plonski:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Smith:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Tseng:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Di Russo:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Cockroft:Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics. Rupon:Pfizer Inc.: Current Employment, Other: own stock/options in the company. Rouy:Sangamo Therapeutics: Current Employment, Other: Shareholder of Sangamo Therapeutics

Stable and Durable Factor Ix Levels in Hemophilia B Patients over 3 Years Post Etranacogene Dezaparvovec Gene Therapy

Etranacogene dezaparvovec (AMT-061) is a recombinant adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) transgene with a liver-specific promoter. Here we report 3-year outcomes from a Phase 2b, open-label, single-dose, single-arm, multi-center trial (NCT03489291) conducted in adults with severe or moderately severe hemophilia B (FIX ≤2%). All participants (n=3) received a single intravenous dose (2×1013 gene copies/kg) and will be followed for 5 years. The primary endpoint of FIX activity ≥5% at 6 weeks was met (mean 30.6% [min–max, 23.9%–37.8%]). Secondary endpoints included bleed frequency, FIX concentrate use, joint health, and adverse events (AEs). All participants required routine FIX prophylaxis and had neutralizing antibodies to AAV5 (mean titer at screening=39) prior to etranacogene dezaparvovec treatment. Post-administration, FIX activity rose to a mean of 40.8% (min–max, 31.3%–50.2%) at year 1, sustained at year 3 (mean 36.9% [min–max, 32.3%–41.5%]). All participants discontinued FIX prophylaxis. Complete elimination of bleeds occurred in 2/3 participants. One participant required on-demand FIX replacement therapy post-treatment per protocol due to elective surgeries, for 2 reported bleeding episodes, and twice for a single selfadministered infusion due to an unreported reason. One participant experienced 2 mild, self-limiting AEs shortly after dosing. During the 3-year study period, there were no clinically significant elevations in liver enzymes, no requirement for steroids, no FIX inhibitor development, and no late emergent safety events in any participant. Etranacogene dezaparvovec was safe and effective in adults with hemophilia B through 3 years post-administration. ClinicalTrials.gov Identifier: NCT03489291

Four-Year Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia Α

Introduction: Hemophilia A is an X-linked ( F8 gene) recessive disorder of hemostasis that results in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)-based gene therapy enables delivery of a modified F8 cDNA, allowing synthesis of functional endogenous FVIII, which prevents bleeding events. We present updated results with nearly 4 years of follow-up on an ongoing gene therapy study in participants with severe hemophilia A (FVIII activity <1%). Methods:The phase 1/2 Alta study (NCT03061201) is a dose-ranging study of giroctocogene fitelparvovec (PF-07055480, previously called SB-525), a recombinant AAV serotype 6 vector encoding a modified B-domain-deleted F8 coding sequence. Four ascending doses of giroctocogene fitelparvovec (9e11, 2e12, 1e13, and 3e13 vg/kg) were infused into adults aged ≥18 years with severe hemophilia A across 4 cohorts (n=2 each). The high-dose (3e13 vg/kg) cohort was expanded to 5 participants. Key endpoints included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. Results: Eleven male participants were enrolled in the study (mean [SD] age, 30.3 [7.8] years; White, 81.8%). As of the cutoff date (May 19, 2023), participants had been followed for 153 to 290 weeks. Two participants left the study after Week 156. Of the remaining, 1 participant had not yet completed 4 years (208 weeks). The most common treatment-related adverse events (AEs) reported in the high-dose cohort (n=5) were elevated liver enzymes and infusion-related reactions: increased alanine aminotransferase (ALT; n=3 [60.0%]), increased aspartate aminotransferase (AST; n=2 [40.0%]), pyrexia (n=3 [60.0%]), and tachycardia (n=2 [40.0%]). Treatment-related serious AEs were reported in 1 participant in the high-dose cohort who experienced hypotension and fever, with onset ≈6 h after infusion; the events fully resolved with treatment. AEs (all causality) of ALT increases requiring ≥7 days of corticosteroids were observed in 4 of 5 participants in the high-dose cohort. ALT elevations were managed with tapering courses of corticosteroids (median duration: 56 days; range: 7-135 days), with maintenance of efficacious levels of FVIII activity. Participants in the high-dose cohort have not required steroids since Week 65, have had ALT values in the normal range (follow-up: 156-208 weeks) and normal findings via liver MRI (follow-up: 104-208 weeks). No participant developed a confirmed inhibitor to FVIII. No thrombotic events or liver masses have been detected. Of the 5 participants in the high-dose cohort, 2 had data available through Week 208 and FVIII activity was maintained in the mild to normal range ( Table), consistent with Week 156 results. Of those without Week 208 data, 2 had data through Week 182. One participant maintained FVIII activity in the mild range (14.1% and 24.1% of normal, measured with a chromogenic and 1-stage assay, respectively); the other had FVIII activity of 3.1% and 7.2%. The remaining participant left the study after Week 156, with FVIII activity maintained in the mild range (11.8% and 22.9%). In the high-dose cohort, the mean annualized total bleeding rate [(number of all bleeding episodes starting 3 weeks after study drug infusion) / (observation period in years)] was 0 for the first year post infusion and 1.2 (SD 2.58) throughout the total duration of follow-up. In this cohort, the participant with the lowest FVIII activity level experienced a total of 22 bleeds, with 21 necessitating treatment (8 traumatic; 7 spontaneous; 6 unknown). The other 4 participants had no or very minimal bleeds, including 1 who experienced a bleed in a target joint. No participants in the high-dose cohort have resumed prophylaxis. Conclusion:A single infusion of giroctocogene fitelparvovec gene therapy in participants with severe hemophilia A remains generally well tolerated over a period of nearly 4 years post infusion, with associated increases in FVIII levels in the moderate to normal range, without sustained AEs and with no AEs associated with increased liver function tests since Week 59. The ongoing phase 3 study (NCT04370054) in a larger cohort will provide more long-term data on the safety and durability of giroctocogene fitelparvovec in participants with moderately severe to severe hemophilia A

Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia a

Abstract Introduction: Hemophilia A is a rare bleeding disorder caused by pathogenic variants in the F8 gene, resulting in insufficient factor VIII (FVIII) activity. Adeno-associated virus (AAV)-mediated gene transfer enables the delivery of a modified functional F8 coding sequence to hepatocytes that subsequently synthesize FVIII at levels that may prevent bleeding events in the absence of exogenous FVIII. We present updated results with nearly 2-year follow-up from the Alta study (NCT03061201), an ongoing gene therapy study in patients with severe hemophilia A (FVIII activity <1%). Methods: The phase 1/2 Alta study is a dose-ranging study of giroctocogene fitelparvovec (PF-07055480 and previously called SB-525), a recombinant AAV serotype 6 vector encoding a modified B-domain-deleted F8 coding sequence. Giroctocogene fitelparvovec was infused into adults aged ≥18 years with severe hemophilia A in 4 cohorts of 2 patients each across 4 ascending doses: 9e11, 2e12, 1e13, and 3e13 vg/kg. The 3e13-vg/kg dose cohort was expanded with 3 additional patients. Key end points included safety, circulating FVIII activity, use of FVIII replacement therapy, and frequency of bleeding events. We present data with nearly 2 years of follow-up from the ongoing Alta study (NCT#03061201; data cutoff date: May 19, 2021). Results: Eleven male patients participated in the study (mean [SD] age, 30.3 [7.8] years; white, 81.8%). As of the cutoff date, one patient had not completed 2 years (104 weeks) of follow-up resulting in patients having been followed for 95 to 195 weeks overall. The most commonly reported treatment-related adverse events (AEs; n/N [%]), included elevated liver enzymes and infusion-related reactions: increased alanine aminotransferase (ALT; 5/11 [45.5%] overall; 3/5 [60.0%] in the 3e13-vg/kg cohort), increased aspartate aminotransferase (AST; 3/11 [27.3%] overall; 2/5 [40.0%] in the 3e13-vg/kg cohort), pyrexia (3/11 [27.3%] overall; 3/5 [60.0%] in the 3e13-vg/kg cohort), and tachycardia (2/11 [18.2%] overall; 2/5 [40.0%] in the 3e13-vg/kg cohort). Treatment-related serious AEs were reported in 1 patient (in the 3e13-vg/kg cohort) who experienced hypotension and fever with onset ≈6 hours after giroctocogene fitelparvovec infusion; the events fully resolved with treatment and did not delay post-infusion discharge the next day. ALT elevations requiring >7 days of corticosteroid treatment were observed in 4 of the 5 patients in the 3e13-vg/kg cohort: elevations in ALT were managed with a tapering course of corticosteroids (median 58 days; range: 11-134 days), with maintenance of efficacious levels of FVIII activity, as evidenced by a lack of bleeding events around the time of corticosteroid treatment and minimal bleeding events afterwards. No patient in the study developed an inhibitor to FVIII, and there have been no thrombotic events and no hepatic masses detected. Patients in the 3e13-vg/kg cohort had mean FVIII activity maintained in the mild to normal range through week 104 for the 4 patients in this cohort with available data at this time point (Table). In this cohort, the annualized bleeding rate [(number of all bleeding episodes starting 3 weeks after study drug infusion)/(observation period in years)] was 0 for the first year postinfusion and 0.9 throughout the total duration of follow-up. In the 3e13-vg/kg cohort, 2 patients experienced a total of 3 bleeding events (2 traumatic; 1 unknown) necessitating treatment with exogenous FVIII; 1 of these events occurred in a target joint. No patients in cohort 4 have resumed prophylaxis. Conclusions: A single infusion of giroctocogene fitelparvovec gene therapy in patients with severe hemophilia A was generally well tolerated with associated increases in FVIII levels in the mild to normal range, without sustained AEs, and with minimal bleeding in the highest-dose cohort (3e13 vg/kg). A phase 3 study (NCT04370054) of giroctocogene fitelparvovec in patients with hemophilia A is ongoing. Figure 1 Figure 1. Disclosures Visweshwar: Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Leavitt: Pfizer: Research Funding; Rigel: Consultancy; HEMA Biologics: Consultancy; BPL: Consultancy; Behring: Consultancy; Syntimmune: Research Funding; Sangamo Therapeutics: Research Funding; BioMarin: Consultancy, Research Funding; Catalys: Consultancy; CSL DOVA: Consultancy; Merck: Consultancy. Konkle: Genentech USA Inc.: Honoraria; Sigilon Therapeutics: Honoraria; BioMarin Pharmaceutical Inc.: Other: Data and safety monitoring; CSL Behring: Other: Data and safety monitoring. Giermasz: ATHN: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy; UniQure: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; Sangamo Therapeutics,: Research Funding; BioMarin: Consultancy, Research Funding. Stine: Applied Stem Cell Therapeutic: Consultancy; BioMarin: Consultancy. Rupon: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Di Russo: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Tseng: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. de los Angeles Resa: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ganne: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Agathon: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Plonski: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Rouy: Sangamo Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Cockroft: Sangamo Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fang: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Arkin: Pfizer Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company

Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the Phase 1/2 Alta study

•Giroctocogene fitelparvovec is the first gene therapy for hemophilia A that uses a recombinant AAV serotype 6-based vector.•Giroctocogene fitelparvovec was generally well tolerated with appropriate clinical management and showed efficacy at the highest dose. Patients with hemophilia A require exogenous factor VIII (FVIII) or non-factor hemostatic agents to prevent spontaneous bleeding events. Adeno-associated virus (AAV) vector–based gene therapy is under clinical investigation to enable endogenous FVIII production. Giroctocogene fitelparvovec is a recombinant AAV serotype 6 vector containing the coding sequence for the B-domain–deleted human F8 gene. In the ongoing phase 1/2, dose-ranging Alta study, 4 sequential cohorts of male participants with severe hemophilia A received a single intravenous dose of giroctocogene fitelparvovec. The primary end points are safety and changes in circulating FVIII activity. Interim results up to 214 weeks after treatment for all participants are presented. Eleven participants were dosed. Increases in alanine and aspartate aminotransferases were the most common treatment-related adverse events (AEs), which resolved with corticosteroid administration. Two treatment-related serious AEs (hypotension and pyrexia) were reported in one participant within 6 hours of infusion and resolved within 24 hours post-infusion. At the highest dose level (3 × 1013 vg/kg; n = 5), the mean circulating FVIII activity level at week 52 was 42.6% (range, 7.8%-122.3%) and at week 104 was 25.4% (range, 0.9%–71.6%) based on a chromogenic assay. No liver masses, thrombotic events, or inhibitors were detected in any participant. These interim 104-week data suggest that giroctocogene fitelparvovec is generally well tolerated with appropriate clinical management and has the potential to provide clinically meaningful FVIII activity levels, as indicated by the low rate of bleeding events in the highest-dose cohort. (ClinicalTrials.gov Identifier: NCT03061201