EFFICACY AND SAFETY OF EPTACOG BETA (RECOMBINANT HUMAN FVIIA) ACCORDING TO AGE IN PERSONS WITH HAEMOPHILIA A/B WITH INHIBITORS UNDERGOING SURGICAL PROCEDURES

Introduction: Eptacog beta (CEVENFACTA®) is a new rFVIIa approved by the EMA for the treatment of bleeding events and prevention of bleeding during surgery in persons with haemophilia A/B with inhibitors (PwHABI) aged ≥12 years (y). Methods: PERSEPT 3 was a Phase 3 (NCT02020369) trial of eptacog beta in PwHABI who required surgical procedures. Eptacog beta was administered at an initial dose of 200μg/kg or 75μg/kg for major or minor procedures respectively. This was followed by 75μg/kg for ≥5 (major procedures) or ≥2 (minor procedures) days. Haemostatic efficacy was assessed using a 4-point scale during the intra and postoperative care period (primary efficacy endpoint was determined by the investigator at the study centre 48±4h after the last dose of eptacog beta, based on the totality of the assessments performed on the patient (pt) at each timepoint). This post-hoc analysis compared the efficacy and safety of eptacog beta by age (pts aged \u3c12 vs ≥12y). Results: Twelve pts were included (\u3c12y: n=5, 1 major and 4 minor procedures; ≥12y: n=7, 5 major and 2 minor procedures). The primary endpoint success proportion was 100% (95% CI: 39.8-100) in pts aged \u3c12y (4 successes, 1 missing) and 71.4% (95% CI: 29.0-96.3) in pts aged ≥12y (5 successes; 2 failures). The intraoperative success proportion was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 59.0-100) for pts aged ≥12y (7 successes). The success proportion 24h post-procedure was 100% (95% CI: 47.8-100) for pts aged \u3c12y (5 successes) and 100% (95% CI: 47.8-100) for pts aged ≥12y (5 successes; 2 missing). Two pts discontinued treatment (1 aged \u3c12y withdrew consent; 1 aged ≥12y due to an adverse event (AE): postprocedural hematoma). One pt experienced 2 serious AEs leading to death, both were considered unrelated to the treatment. No allergic or thrombotic events occurred; no neutralising antibodies were detected. Antifibrinolytics were used concomitantly with eptacog beta in 4 patients without any safety concerns. Discussion/Conclusion: This post-hoc subgroup analysis shows that eptacog beta is effective and well-tolerated in perioperative care irrespective of patient age (\u3c12 vs ≥12y), supporting the use of eptacog beta for bleed management (prevention and treatment) in major and minor surgical procedures in all PwHABI

Potentiation of the anti-tumour effects of Photofrin®-based photodynamic therapy by localized treatment with G-CSF

Photofrin®-based photodynamic therapy (PDT) has recently been approved for palliative and curative purposes in cancer patients. It has been demonstrated that neutrophils are indispensable for its anti-tumour effectiveness. We decided to evaluate the extent of the anti-tumour effectiveness of PDT combined with administration of granulocyte colony-stimulating factor (G-CSF) as well as the influence of Photofrin®and G-CSF on the myelopoiesis and functional activity of neutrophils in mice. An intensive treatment with G-CSF significantly potentiated anti-tumour effectiveness of Photofrin®-based PDT resulting in a reduction of tumour growth and prolongation of the survival time of mice bearing two different tumours: colon-26 and Lewis lung carcinoma. Moreover, 33% of C-26-bearing mice were completely cured of their tumours after combined therapy and developed a specific and long-lasting immunity. The tumours treated with both agents contained more infiltrating neutrophils and apoptotic cells then tumours treated with either G-CSF or PDT only. Importantly, simultaneous administration of Photofrin®and G-CSF stimulated bone marrow and spleen myelopoiesis that resulted in an increased number of neutrophils demonstrating functional characteristics of activation. Potentiated anti-tumour effects of Photofrin®-based PDT combined with G-CSF observed in two murine tumour models suggest that clinical trials using this tumour therapy protocol would be worth pursuing. © 2000 Cancer Research Campaig

Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function

Early stages of viral infections are associated with local recruitment and activation of dendritic cells (DC) and NK cells. Although activated DC and NK cells are known to support each other's functions, it is less clear whether their local interaction in infected tissues can modulate the subsequent ability of migrating DC to induce T cell responses in draining lymph nodes. In this study, we report that NK cells are capable of inducing stable type 1-polarized "effector/memory" DC (DC1) that act as carriers of NK cell-derived helper signals for the development of type 1 immune responses. NK cell-induced DC1 show a strongly elevated ability to produce IL-12p70 after subsequent CD40 ligand stimulation. NK-induced DC1 prime naive CD4+ Th cells for high levels of IFN-gamma, but low IL-4 production, and demonstrate a strongly enhanced ability to induce Ag-specific CD8+ T cell responses. Resting NK cells display stringent activation requirements to perform this novel, DC-mediated, "helper" function. Although their interaction with K562 cells results in effective target cell killing, the induction of DC1 requires a second NK cell-activating signal. Such costimulatory signal can be provided by type I IFNs, common mediators of antiviral responses. Therefore, in addition to their cytolytic function, NK cells also have immunoregulatory activity, induced under more stringent conditions. The currently demonstrated helper activity of NK cells may support the development of Th1- and CTL-dominated type 1 immunity against intracellular pathogens and may have implications for cancer immunotherapy.Mailliard, Robbie B ; Son, Young-ik ; Redlinger, Richard ; Coates, Patrick T ; Giermasz, Adam ; Morel, Penelope A ; Storkus, Walter J ; Kalinski, Pawe

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

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

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

Valoctocogene roxaparvovec gene therapy for hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study. METHODS: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results. RESULTS: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants. CONCLUSIONS: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.)