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.
Background: Etranacogene dezaparvovec is an investigational gene therapy for hemophilia B (HB) comprising an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with a liver specific promoter. In a Phase 2b study, a single dose of etranacogene dezaparvovec provided mean FIX activity of 41.0% sustained at 1yr post-dose in 3 participants (pts). Although most gene therapy clinical studies exclude pts with pre-existing neutralizing antibodies (NAbs) to the capsid serotype, early clinical studies and nonhuman primate data suggest that generally prevalent titers of anti-AAV5 NAbs may not preclude successful transduction with etranacogene dezaparvovec. Aims: A Phase 3, Health Outcomes with Padua gene; Evaluation in Hemophilia B (HOPE-B; NCT03569891) was established to further assess efficacy and safety of etranacogene dezaparvovec in adults with HB with a wide range of pre-existing NAbs to AAV5. Here we report outcomes at 26 weeks (wks). Methods: HOPE-B is a Phase 3, open-label, single-dose, single-arm, multi-national trial in adult males with severe or moderate-severe HB (FIX≤2%). All pts received routine FIX prophylaxis prior to study. Pts were not excluded based on pre-existing NAbs to AAV5. Pts entered a prospective lead-in period of at least 6 months during which bleeding/factor use was monitored, then received a single intravenous dose of etranacogene dezaparvovec (2x1013 gc/kg). Pts will be followed for 5yrs. Primary endpoints comprised FIX activity (one stage) at 26 and 52wks after dosing and 52wk annualized bleeding rate. For pts with no clean post-treatment FIX samples (≥10d post exogenous FIX), factor activity was imputed as baseline value based on historic disease severity. Secondary endpoints include factor replacement use, adverse events (AEs), and reactive use of corticosteroids. Results: 75 pts were screened, of whom 67 entered lead-in. 54 pts were dosed (44 severe, 10 moderately severe HB) and completed 26wks of follow-up. Mean age (±SD) was 41.5 (15.8) yrs. 38/54 pts (70.4%) had bleeds (n=123) during the lead-in despite prophylaxis, and 23/54 (42.6%) had NAbs to AAV5 at baseline (max titer: 3212.3). Following treatment, FIX activity increased rapidly to a mean (SD; min,max) of 37.2% (±19.6; 1.0, 97.1) at wk26, representing a mean (SD; min,max) change from baseline of 36.0% (±19.7; 0, 96.1 p<0.0001, confirmed by per-protocol sensitivity analysis). No correlation of pre-existing NAbs with FIX activity was identified up to a titer of 678.2; n=52, R2 = 0.078); a single pt had a NAb titer of 3212.3 and did not respond. In addition to this pt, one other pt received a partial dose and remained on prophylaxis; all other pts (96.3%) successfully discontinued routine prophylaxis. 39/54 (72.2%) pts reported 0 bleeds in the first 26wks post-treatment; 15 pts reported a total of 21 bleeds. Mean (SD) annualized FIX consumption (IU/yr/pt) was 292,304 (±171,079) during lead-in, decreasing to 12,622 (±36,466) at wk26 (96.0% reduction, N=54). Overall, 37/54 (68.5%) pts had any treatment-related AE post-treatment, the majority of which were mild (81.5%). No deaths occurred and no treatment-related SAEs were reported. 7 pts had infusion-related reactions; the infusion was discontinued in 1 pt. Treatment-related elevations in liver enzymes were reported in 9 pts and received steroids per protocol. All discontinued steroid use prior to wk26 and FIX activity was preserved in the mild range. In addition to these, the most frequent treatment-related AEs were headache (13.0%) and influenza-like illness (13.0%). No inhibitors to FIX were reported. No relationship between safety and NAbs was observed. Conclusions: The first co-primary endpoint of this study was met. This is the first report of a Phase 3 study in HB and the largest gene therapy trial cohort to date. Following a single dose of etranacogene dezaparvovec, FIX activity increased, without the need for prophylactic immunosuppression, into the mild-to-normal range at 26wks in pts with severe/moderately severe HB. Importantly, this included pts with titers of pre-existing anti-AAV5 NAbs. Pts were able to discontinue prophylaxis and bleeding was abolished in the majority. The safety profile was consistent with early phase AAV5 studies and together these data support a favorable safety and efficacy profile for etranacogene dezaparvovec Disclosures Pipe: HEMA Biologics: Consultancy, Other; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; ApcinteX: Consultancy; Bayer: Consultancy, Other: Contracted Research; BioMarin: Consultancy, Other: Contracted Research; Takeda: Consultancy; uniQure: Consultancy, Other; Siemens: Other; Pfizer: Consultancy; Freeline Therapeutics: Consultancy, Other: Contracted Research; Novo Nordisk: Consultancy, Other: Contracted Research; Roche/Genentech: Consultancy, Other: Contracted Research; Sangamo Therapeutics: Consultancy; Sanofi Genzyme: Consultancy, Other; Spark Therapeutics: Consultancy. Recht:CSL Behring: Consultancy, Other: personal fees; Genentech: Consultancy, Other: personal fees, Research Funding; Pfizer: Consultancy, Other: personal fees, Research Funding; BioMarin: Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; uniQure: Consultancy, Other: personal fees, Research Funding; Novo Nordisk: Consultancy, Other: personal fees, Research Funding; Spark: Research Funding; Bayer: Research Funding; Grifols: Research Funding; Hema Biologics: Consultancy, Research Funding; LFB: Research Funding; Octapharma: Research Funding; Catalyst Biosciences: Consultancy; Kedrion: Consultancy; Sanofi: Consultancy, Research Funding. Key:Uniqure: Consultancy; Grifols: Research Funding; Takeda: Research Funding; Novo Nordisk: Other: Chair of Grants Committee. Leebeek:Shire/Takeda: Research Funding; uniQure: Consultancy; Shire/Takeda: Consultancy; BioMarin: Consultancy; SOBI: Other: Travel grant; Roche: Other: DSMB member for a study; CSL Behring: Research Funding. Castaman:Bayer, Roche, Sobi, Grifols, Novo Nordick, Werfen, Kedrion: Consultancy, Honoraria, Speakers Bureau; CSL Behring, Pfizer, Sobi: Research Funding; Ablynx, Alexion, Bayer, Takeda, CSL Behring, Novo Nordisk, Pfizer, Roche,Sanofi, SOBI, uniQure: Membership on an entity's Board of Directors or advisory committees. Lattimore:uniQure: Other: Study Steering Committee member. Van Der Valk:Baxalta: Research Funding. Peerlinck:Bayer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Roche: Research Funding; Sobi: Consultancy; Takeda: Consultancy, Research Funding. Coppens:Roche: Research Funding; Portola/Alexion: Research Funding; Sanquin Blood Supply: Research Funding; uniQure: Research Funding; NovoNordisk: Consultancy; Pfizer: Consultancy; Sobi: Consultancy; Medcon International: Consultancy; MEDtalks: Consultancy; Bayer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Daiichi Sankyo: Research Funding. O'Connell:uniQure: Consultancy; F. Hoffmann-La Roche Ltd, Novo Nordisk, SOBI: Speakers Bureau; SOBI: Research Funding. Pasi:Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; uniQure: Other: Grants and nonfinancial support , Research Funding; ApcinteX: Consultancy, Other: Personal fees ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Roche: Honoraria, Other; Sobi: Consultancy, Honoraria, Other; Tremeau: Consultancy. Kampmann:Uniqure: Research Funding, Speakers Bureau; Shire Pharmaceuticals: Speakers Bureau. Meijer:Pfizer: Research Funding; Sanquin: Speakers Bureau; Bayer: Speakers Bureau; Sanquin: Research Funding; Bayer: Research Funding; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. von Drygalski:Biomarin: Consultancy; Bioverativ/Sanofi Genzyme: Consultancy; NovoNordisk: Consultancy; Pfizer: Consultancy; uniQure: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees. Young:Genentech/Roche, Grifols, and Takeda: Research Funding; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Bayer, CSL Behring, Freeline, UniQure: Consultancy. Hermans:WFH: Other; EAHAD: Other; LFB: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau. Astermark:Bayer, CSL Behring, Novo Nordisk, Octapharma, Roche, Sobi, Spark, Takeda, uniQure: Consultancy; uniQure: Research Funding. Klamroth:Bayer: Consultancy, Research Funding, Speakers Bureau; Biomarin: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche/Chugai: Consultancy, Speakers Bureau; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Biotest: Speakers Bureau; LEO: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lemons:uniQure: Research Funding. Visweshwar:Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Escobar:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biomarin, Genetech/Roche, CSL Behring, Kedrion, Magellan Healthcare: Honoraria. Gomez:Global Blood Therapeutics: Speakers Bureau. Kruse-Jarres:CSL Behring, Genentech, Inc., Spark: Research Funding; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Honoraria; F. Hoffmann-La Roche Ltd: Speakers Bureau; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Consultancy. Kotowski:uniQure: Research Funding. Quon:Orthopaedic Institute for Children: Current Employment; Bayer: Honoraria; Biomarin: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Octapharma: Honoraria; Shire/Takeda: Speakers Bureau. Wang:Bayer: Honoraria; Takeda: Honoraria; Genentech: Honoraria; Biomarin: Honoraria; CSL Behring: Honoraria; Bioverativ Inc: Honoraria; Catalyst Biologics: Consultancy; NovoNordisk: Consultancy; Hema biologics / LFB: Consultancy. Wheeler:Takeda: Membership on an entity's Board of Directors or advisory committees; uniQure: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Sawyer:uniQure: Current Employment, Current equity holder in publicly-traded company. Verweij:uniQure: Current Employment. Colletta:uniQure: Current Employment. Bajma:uniQure: Current Employment. Gut:uniQure: Current Employment. Miesbach:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Freeline: Consultancy, Membership on an entity's Board of Directors or advisory committees; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; uniQure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Etranacogene dezaparvovec is an investigational gene therapy
BackgroundWe report the first case to our knowledge of a patient with relapsed/refractory classical hodgkin lymphoma and liver failure with encephalopathy along with human immunodeficiency virus/acquired immunodeficiency syndrome infection, successfully treated with nivolumab without major side effects and encouraging prolonged disease control.Case presentationIn December 2015, at the time of the patient’s progression from his Hodgkin lymphoma after fourth line treatment, he developed persistent fevers, abdominal distension, jaundice and worsening of his liver function tests. Magnetic resonance imaging of abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions, splenomegaly with multiple splenic nodules and several new mediastinal, intraperitoneal and retroperitoneal lymphadenopathy. In accordance with the patient’s wishes before admission, and after agreement with the family, nivolumab (3 mg/kg every 2 weeks) was given. Of note, antiretroviral therapy was on hold due to liver function tests, his viral load was undectable and cluster of differentiation 4 counts were 103/uL at the time of nivolumab administration. One week after the first dose of nivolumab both his hepatic encephalopathy and constitutional symptoms started to improve, and after 2 doses, (January 2016) his LFTs were almost back to normal. After 5 months of nivolumab treatment (10 doses), restaging (computerized tomography scans of neck, chest, abdomen, pelvis) done on May 2016 showed resolution of hepatosplenomegaly with two residual small hepatic lesions, heterogeneous spleen with no splenic lesions, and stable non-enlarged retroperitoneal lymph nodes without intraabdominal lymphadenopathy; consistent with partial response.ConclusionsWe report a case of a patient with human immunodeficiency virus/acquired immunodeficiency syndrome -related relapsed/refractory classical Hodgkin lymphoma and acute liver failure with encephalopathy successfully treated with nivolumab after failing all standard therapeutic options. Unlike classic cytotoxic chemotherapy, which relies on preserved organ function to ameliorate potential severe side effects (i.e. myelosuppression), elimination of monoclonal antibodies is fairly independent of baseline renal and hepatic function since they are usually metabolized by circulating phagocytes and/or by their target antigen-expressing cell.
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.
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