Abstract: Background Hemophilia is a rare bleeding disorder characterized by deficiency of FVIII or FIX resulting in ineffective clot formation due to impaired thrombin generation. Fitusiran is a subcutaneously (SC) administered investigational siRNA therapeutic agent which targets antithrombin to enhance thrombin generation potential and rebalance hemostasis in people with hemophilia (PwH), irrespective of inhibitor status. Here, we present results from a Phase 3 study of the efficacy and safety of fitusiran prophylaxis compared with on-demand (OD) treatment with factor concentrates in PwH A or B without inhibitors (ATLAS-A/B; NCT03417245). Methods This Phase 3, multicenter, multinational, randomized, open-label study evaluated the efficacy and safety of fitusiran in males aged ≥12 years with severe hemophilia A or B without inhibitors, previously treated OD. Eligible participants (pts) were randomized 2:1 to receive either once-monthly 80 mg SC fitusiran prophylaxis (fitusiran arm) or OD factor concentrates for treatment of bleeding episodes (OD arm) for a treatment period of 9 months. The primary endpoint was annualized bleeding rate (ABR) in the efficacy period (Day 29 post-first fitusiran dose up to Day 246). Secondary endpoints included annualized spontaneous bleeding rate (AsBR) and annualized joint bleeding rate (AJBR) in the efficacy period and health-related quality of life (HRQoL) in the treatment period, measured by Haem-A-QoL. Safety and tolerability were assessed throughout the study. Results Overall, 120 pts were randomized (fitusiran arm n=80; OD arm n=40); 79 pts (98.8%) in the fitusiran arm and 37 pts (92.5%) in the OD arm completed the study. A total of 93 pts had hemophilia A (fitusiran arm n=62, OD arm n=31) and 27 pts had hemophilia B (fitusiran arm n=18, OD arm n=9). Baseline demographics and characteristics were similar in both arms. Median observed ABR was 0.0 (IQR, 0.0 to 3.4) in the fitusiran arm and 21.8 (IQR, 8.4 to 41.0) in the OD arm; 40 pts (50.6%) in the fitusiran arm experienced no bleeds that required treatment with OD factor concentrates. A significant reduction in estimated ABR was achieved in the fitusiran arm vs the OD arm (89.9% reduction [95% CI, 84.1% to 93.6%], p & lt;0.0001; Table). Median observed AsBR was 0.0 (IQR, 0.0 to 1.7) in the fitusiran arm and 16.1 (IQR, 3.4 to 27.6) in the OD arm. A significant reduction in estimated AsBR was achieved in the fitusiran arm vs the OD arm (91.7% reduction [95% CI, 85.9% to 95.1%], p & lt;0.0001; Table). Median observed AJBR was 0.0 (IQR, 0.0 to 3.4) in the fitusiran arm and 15.9 (IQR, 4.2 to 33.5) in the OD arm. There was a significant reduction in estimated AJBR in the fitusiran arm vs the OD arm (90.3% reduction [95% CI, 83.9% to 94.1%], p & lt;0.0001; Table). A significant improvement was also achieved in the transformed total and physical health score in the fitusiran arm vs the OD arm (LS mean difference -7.07 [95% CI, -11.23 to -2.90], p=0.0011; -19.75 [95% CI, -27.00 to -12.50] , p & lt;0.0001, respectively). Seventy-nine pts received at least 1 dose of fitusiran and 40 patients were randomized to the OD arm and included in the safety analysis. Overall, 62 pts (78.5%) in the fitusiran arm and 18 pts (45%) in the OD arm experienced ≥1 treatment emergent adverse event (TEAE). A total of 5 treatment emergent serious adverse events (TESAEs) were reported in 5 pts (6.3%) in the fitusiran arm and 9 TESAEs were reported in 5 pts (12.5%) in the OD arm. TESAEs in the fitusiran arm included cholelithiasis (2 pts, 2.5%), cholecystitis, lower respiratory tract infection, and asthma (1 pt each, 1.3%). In the fitusiran arm, 2 pts (2.5%) experienced TEAEs that resulted in fitusiran discontinuation (cholecystitis and increased alanine aminotransferase). No TEAEs of thrombosis and no fatal TEAEs were reported. Conclusions All key primary and secondary endpoints were met in this Phase 3 study. Specifically, once-monthly 80 mg SC fitusiran prophylaxis demonstrated a significant reduction in ABR, AsBR and AJBR (all ~90%) in people with severe hemophilia A or B without inhibitors compared with OD treatment. This reduction in bleeding was associated with a meaningful improvement in HRQoL. Reported TESAEs were generally consistent with previously identified risks of fitusiran. With the aim of further enhancing the benefit-risk profile of fitusiran, a revised regimen with reduced dose and frequency is currently being evaluated in ongoing clinical studies. Figure 1 Figure 1. Disclosures Srivastava: Roche: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board, Research Funding; Sanofi: Other: Advisory Board, Research Funding; Pfizer: Other: Advisory Board, Research Funding; Takeda: Other: Advisory Board, Research Funding; Bayer Healthcare: Other: Grant Review & Awards Committee. Rangarajan: Sanofi: Other: Advisory Board; Pfizer: Other: Advisory Board; Reliance Life Sciences: Consultancy; Takeda: Other: Advisory Board, Conference Support, Speakers Bureau. Kavakli: Pfizer, Bayer, Takeda, Roche, Novo Nordisk: Honoraria; Pfizer, Bayer, Roche, Novo Nordisk, Takeda: Speakers Bureau; Roche, Bayer, Pfizer, Novo Nordisk, Takeda: Membership on an entity's Board of Directors or advisory committees. Klamroth: Bayer, Leo: Research Funding; Bayer, Biotest, Biomarin, BMS, CSL Behring, Daiichi Sankyo, Leo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, SOBI, Takeda: Honoraria; Bayer, Biotest, Biomarin, BMS, CSL Behring, Daiichi Sankyo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, SOBI, Takeda: Speakers Bureau. Kenet: Alnylam: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Opko Biologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding; Nat'l Hemophilia Ctr and Coagulation Unit and Amalia Biron Res Inst of Thromb & Hemost, Sheba Medical Ctr, Tel Hashomer, Israel: Current Employment; BioMarin Pharmaceutical: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Uniquore: Honoraria, Membership on an entity's Board of Directors or advisory committees; BPL: Research Funding. Khoo: NSW Health Pathology: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau. You: Eulji University Hospital: Current Employment. Malan: PHOENIX Pharma (Pty) Ltd, Qgeberha, South Africa: Current Employment, Research Funding; St Francis Hospital, Qgeberha, South Africa: Membership on an entity's Board of Directors or advisory committees. Frenzel: Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; CSL Behring: Research Funding. Stasyshyn: CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Shire: Consultancy, Honoraria, Research Funding; Institute of Blood Pathology and Transfusion Medicine of National Academy of Medical Sciences of Ukraine: Current Employment; Sanofi: Honoraria, Research Funding; Roche: Speakers Bureau; LFB: Honoraria, Research Funding. Poloskey: Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company; WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Mei: Sanofi: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties. Pipe: Sangamo Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; ASC Therapeutics: Consultancy, Other: Scientific Advisory Board; Apcintex: Consultancy; Bayer: Consultancy; Biomarin: Consultancy; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; Freeline: Consultancy; Grifols: Consultancy; HEMA Biologics: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy; GeneVentiv: Consultancy, Membership on an entity's Board of Directors or advisory committees; YewSavin: Research Funding; Siemens: Research Funding.

Abstract: Purpose: Ad5.SSTR/TK.RGD is an infectivity-enhanced adenovirus expressing a therapeutic thymidine kinase suicide gene and a somatostatin receptor (SSTR) that allows for noninvasive gene transfer imaging. The purpose of this study was to identify the maximum tolerated dose (MTD), toxicities, clinical efficacy, and biologic effects of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Experimental Design: Eligible patients were treated intraperitoneally for 3 days with 1 × 109 to 1 × 1012 vp/dose of Ad5.SSTR/TK.RGD followed by intravenous ganciclovir for 14 days. Toxicity and clinical efficacy were assessed using Common Toxicity Criteria (CTC) Adverse Events grading and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Imaging using In-111 pentetreotide was obtained before and after treatment. Tissue samples were obtained to evaluate for gene transfer, generation of wild-type virus, viral shedding, and antibody response. Results: Twelve patients were treated in three cohorts. The most common vector-related clinical toxicities were grade I/II constitutional or pain symptoms, experienced most often in patients treated at the highest dose. MTD was not identified. Five patients showed stable disease; all others experienced progressive disease. One patient with stable disease experienced complete resolution of disease and normalization of CA125 on further follow-up. Imaging detected increased In-111 pentetreotide retention in patients treated at the highest dose. Ancillary studies showed presence of Ad5.SSTR/TK.RGD virus and HSV1-tk expression in ascites samples collected at various time points in most patients treated within the higher dose cohorts. Conclusions: This study shows the safety, potential efficacy, and possible gene transfer imaging capacity of Ad5.SSTR/TK.RGD in patients with recurrent gynecologic cancer. Further development of this novel gene therapeutic appears to be warranted. Clin Cancer Res; 18(12); 3440–51. ©2012 AACR.

Abstract: What's already known about this topic? Short fetal femur length is associated with non‐genetic and genetic causes. Exome sequencing (ES) is a powerful tool to identify pathogenic variants, and has been widely adopted in prenatal diagnosis. ES has a variable diagnostic yield for various fetal structural abnormalities. What does this study add? Deep phenotyping facilitates bioinformatics analysis of ES in fetal skeletal dysplasias. Panel sequencing and ES have a high diagnostic yield for highly selected fetuses with skeletal dysplasias in the first and second trimesters.

Abstract: Humoral autoimmunity is central to the development of systemic lupus erythematosus (SLE). Complement receptor type 2 (CR2)/CD21 plays a key role in the development of high-affinity Abs and long-lasting memory to foreign Ags. When CR2 is bound by its primary C3 activation fragment–derived ligand, designated C3d, it coassociates with CD19 on B cells to amplify BCR signaling. C3d and CR2 also mediate immune complex binding to follicular dendritic cells. As the development of SLE involves subversion of normal B cell tolerance checkpoints, one might expect that CR2 ligation by C3d-bound immune complexes would promote development of SLE. However, prior studies in murine models of SLE using gene-targeted Cr2−/− mice, which lack both CR2 and complement receptor 1 (CR1), have demonstrated contradictory results. As a new approach, we developed a highly specific mouse anti-mouse C3d mAb that blocks its interaction with CR2. With this novel tool, we show that disruption of the critical C3d–CR2 ligand-receptor binding step alone substantially ameliorates autoimmunity and renal disease in the MRL/lpr model of SLE.