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Background: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. Methods: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. Results: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P

Introduction Standardized and disease-specific patient-reported outcome (PRO) instruments assessing pain, functional impairment and health-related quality of life (HRQoL) in people with haemophilia (PWH) have been used in studies, but infrequently in comprehensive care settings for individual assessment or treatment planning. Aim To assess the impact of pain and functional impairment on HRQoL in PWH. Methods P-FiQ enrolled 381 adult PWH with a history of joint pain/bleeding and included 5 PROs and a clinical joint evaluation (Hemophilia Joint Health Score v2.1 [HJHS]). Results Median age was 34 years; 49.9% reported a history of joint procedure or surgery. On EQ-5D-5L, most reported problems with mobility (61.4%), usual activities (53.2%) and pain/discomfort (76.1%). On Brief Pain Inventory v2 Short Form, median worst pain (range 0-10) was 6, least pain 1, average pain 3 and current pain 2. Ankles were most frequently reported as the most painful joints (37.4%), followed by knees (23.7%) and elbows (18.9%). On International Physical Activity Questionnaire, 51% reported no activity in the prior week. On SF-36v2 health survey, median subscores were worse for 4 physical health domains vs 4 mental health domains. Among Hemophilia Activities List domains (range 0 [worst]-100 [best]), functions of the legs (median, 66.7) and lying/sitting/kneeling/standing (median, 67.5) were most impacted and self-care least impacted (median, 100.0). On HJHS, ankle scores (median, 6.0; range, 0-40) were worse than elbow/knee scores (median, 4.0/4.0). Results were consistent across PROs/HJHS. Conclusion Data demonstrate challenges of predominantly ankle/knee pain and lower extremity functional impairment in US adult PWH, affecting HRQoL across PROs/HJHS.

Etranacogene dezaparvovec (AMT-061) is a recombinant AAV5 vector including a gene cassette containing the factor IX (FIX) Padua variant under the control of a liver-specific promoter. A phase 2b study was conducted to confirm that a single dose of 2 × 1013 genome copies per kilogram of etranacogene dezaparvovec will result in FIX activity ≥5% 6 weeks after dosing. Secondary end points included FIX activity at other time points, bleed frequency, FIX replacement, and safety. Etranacogene dezaparvovec was administered as a single IV infusion to 3 adults with severe to moderately severe hemophilia B. Before treatment, participants had low levels of preexisting neutralizing antibodies to AAV5. This article reports a planned 26-week interim assessment. At week 6, mean FIX activity was 31% (23.9%-37.8%), increasing to 47% (33.2%-57.0%) at 26 weeks, with 2 subjects exhibiting sustained activity >40%. Consistent with the FIX activity, etranacogene dezaparvovec was associated with a complete bleed cessation with no need for FIX replacement therapy up to 26 weeks. Etranacogene dezaparvovec was generally well tolerated. No clinically significant elevations in levels of liver enzymes or inflammatory markers were observed, and no use of corticosteroids related to treatment was required. In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay. Consistency of results in the 3 participants supported an expanded evaluation of the safety/efficacy of etranacogene dezaparvovec in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase 3 trial. The current trial was registered at www.clinicaltrials.gov as #NCT03489291.

The Hemostasis and Thrombosis Research Society Registry was used to monitor the postapproval use and safety of recombinant activated factor VII (rFVIIa). The objective of this article is to evaluate the data from the Hemostasis and Thrombosis Research Society Registry related to rFVIIa-treated bleeding episodes in patients with acquired hemophilia. For each rFVIIa-treated bleeding episode, the initial dose, total dose, average infused dose, number of doses, and treatment duration were calculated. Efficacy was assessed on a three-point scale. Out of the 166 registered patients with acquired hemophilia, 110 patients were treated for 237 bleeding episodes (139 rFVIIa treated); the majority (70%) were in patients older than 60 years. The most frequently reported bleeding locations were subcutaneous (40%) and mucosal (32%). Subcutaneous bleeding episodes were more commonly reported in women (55% vs. 40% men) and white patients (44 vs. 27% black). Of the 139 rFVIIa-treated bleeding episodes, rFVIIa was used as first-line treatment in 127 bleeding episodes. The median initial dose was 90 μg/kg; the median total dose per episode was 333.5 μg/kg. Physician-rated efficacy of rFVIIa for each bleeding episode was reported as 'bleeding stopped' in 85% of bleeding episodes, 'bleeding slowed' in 11% of bleeding episodes, 'no improvement' in 4% of bleeding episodes, and was not documented in 1 bleeding episode. One thromboembolic event was reported; transient neurologic symptoms were reported in a 31-year-old postpartum patient after 110 doses of rFVIIa. Adequate hemostasis was provided for most rFVIIa-treated bleeding episodes at doses largely conforming to the package insert. No major safety concerns were reported.

The Hemostasis and Thrombosis Research Society (HTRS) Registry was used to monitor the postapproval use of recombinant factor VIIa. The objective of this manuscript is to provide key insights on the demographics of patients with acquired hemophilia in the HTRS Registry. Acquired hemophilia patient registration in HTRS captured age; sex; comorbidities and predisposing conditions; first bleeding location; laboratory parameters; exposure to blood products, factor, and bypassing agents; and initiation of immune suppression/tolerance therapy. Overall, 166 patients with acquired hemophilia were registered in HTRS (83 women, 73 men, median age 70 years); the majority were non-Hispanic whites (61.4%). The most common comorbidities were autoimmune disease (28.4%) and malignancy (14.5%). The most common first site of bleeding was subcutaneous (27.1%); this was more common in whites (29.1%) than blacks (12.5%) and in non-Hispanics (26.4%) than Hispanics (11.8%). Blood product exposure was reported for 33.1% of patients; the most commonly reported product was packed red blood cells (28%). Of the 57 patients with outcome data available for immune tolerance therapy, 26 patients (46%) reported successful treatment, 13 reported unsuccessful treatment (23%), and 18 (32%) were receiving active treatment at the time of registration. The HTRS Registry final analysis provides the only current comprehensive look at acquired hemophilia in the US population, including details on underlying autoimmune diseases and malignancies. Pertinent to recognition and diagnosis of the disease, subcutaneous bleeding as a presenting bleeding symptom was more common in white and non-Hispanic individuals.

Objective: Adult growth hormone deficiency (AGHD) results in physiologic impairments that may reduce quality of life and negatively impact body composition. AGHD can be treated with recombinant human growth hormone (GH). This study analyzes AGHD patients enrolled in the American Norditropin® Studies: Web-Enabled-Research (ANSWER) Program/NovoNet, a U.S. observational noninterventional study of patients treated with Norditropin® (somatropin lrecombinant DNA origin] injection) at the discretion of their physicians. Methods: Data were evaluated for GH stimulation test (GHST) usage and Norditropin® doses over 4 years. Results: Adults (N = 468) with isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were evaluated. The most commonly used GHSTs were arginine + L-dopa (27%; mostly a single center) and glucagon (25%; most frequent test after 2009). The percent of patients meeting recommended test-specific cut points varied from 32 to 100%, depending on the GHST used. Mean baseline GH doses were higher for MPHD patients and for younger patients in both IGHD and MPHD groups. Conclusion: MPHD was more common than IGHD. Mean GH doses were higher in younger patients, consistent with a transition from higher pediatric to lower adult dosing. Over time, glucagon became the most popular GHST. The use, in some patients, of other GHSTs with cut points, as well as starting doses not consistent with current recommendations, highlights the need for continued education regarding treatment guidelines for AGHD. Abbreviations: AACE = American Association of Clinical Endocrinologists AGHD = adult growth hormone deficiency ANSWER = American Norditropin® Studies: Web-Enabled-Research BMI = body mass index GH = growth hormone GHD = growth hormone deficiency GHRH = growth hormone-releasing hormone GHST = growth hormone stimulation test IGF-1 = insulin-like growth factor-1 IGHD = isolated growth hormone deficiency ITT = insulin tolerance test KIMS = Pfizer International Metabolic Database MPHD = multiple pituitary hormone deficiency TES = The Endocrine Society

ObjectiveTo examine whether attention-deficit/hyperactivity disorder (ADHD) stimulant medication modified the linear growth response to growth hormone (GH) treatment in children enrolled in the American Norditropin Studies: Web-Enabled Research Program.Study designShort, GH treatment-naive children with or without GH deficiency (GHD) received GH therapy. A subset also received ADHD stimulant medication (n = 1190), and others did not (n = 7230). Linear mixed models (adjusted means) examined height SDS (HSDS) and body mass index (BMI) SDS from baseline through year 4. Analyses were repeated with ADHD groups matched for baseline age, height, weight, BMI, and sex. Groups with and without GHD were compared between ADHD groups.ResultsAdjusted change in HSDS for the group receiving ADHD stimulant medication was slightly lower than that for patients not receiving stimulant medication at years 1 to 4 (P −2. Year 4 adjusted change in BMI SDS was greater in the patients receiving ADHD stimulant medication compared with both groups not receiving ADHD stimulant medication (P

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 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

Background: Gene therapy for hemophilia offers the possibility to ameliorate disease severity to a mild or functionally curative state through a single administration. Etranacogene dezaparvovec (AMT-061) is an investigational gene therapy for hemophilia B comprising an adeno associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with liver specific promoter. Aims: We have previously shown a single dose of etranacogene dezaparvovec to provide sustained FIX activity into the mild-to normal range for up to 52 weeks post-dose in participants with severe or moderate-severe hemophilia B. This time, 2 years of follow-up data will be presented for the first time. Methods: A Phase 2b, open-label, single-dose, single-arm, multi-center trial (NCT03489291) in adult hemophilia B subjects. Interestingly, participants were not excluded based on neutralizing antibodies to AAV5. All subjects received a single intravenous dose of etranacogene dezaparvovec (2x1013 gc/kg) and will be followed for 5-years. The primary endpoint was FIX activity at Week 6. Secondary endpoints include e-diary recordings of bleeds and FIX concentrate use, laboratory parameters, joint health, patient reported outcomes, and adverse events (AEs). Results: All participants had FIX ≤1% (severe or moderately-severe FIX deficiency), required routine FIX prophylaxis, and had neutralizing activity to AAV5 at baseline. Following AMT-061 treatment, FIX activity increased rapidly to a mean of 31% at Week 6. At Week 52, mean FIX activity increased further to 41% with FIX activity levels of 50%, 31% and 41% in participants 1-3 respectively. There was no relationship between the presence of anti-AAV5 NAbs and response to etranacogene dezaparvovec. As of 52 weeks, there were no bleeds post-treatment and no requirement for FIX replacement aside from protocol-specified use for perioperative management in participant 3. There were no clinically significant elevations in liver enzymes and no participants required steroids related to the treatment. One participant experienced 2 mild AEs possibly related to treatment shortly after dosing (self-limiting headache and slightly elevated CRP). One patient had hip surgery due to worsening of pre-existing avascular necrosis deemed unrelated by investigator to etranacogene dezaparvovec and received FIX per protocol according to standard clinical practice. No participant developed inhibitors to FIX. Updated results to 2 years of follow-up will be presented with the main focus on FIX activity, FIX replacement therapy use and reported bleeds. Conclusions: Patients with AAV5 NAbs were included in the Phase 2b etranacogene dezaparvovec trial and have shown sustained FIX activity into the mild-to normal range. All participants were able to discontinue routine prophylaxis, and there have been no bleeds post-treatment with etranacogene dezaparvovec. Disclosures Giermasz: BioMarin: Consultancy, Research Funding, Speakers Bureau; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; uniQure: Consultancy, Research Funding; Sangamo Therapeutics: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau. Castaman:Alexion: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ablynx: Honoraria; Baxalta/Shire: Honoraria; Bayer: Honoraria; Uniqure: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kedrion: Speakers Bureau; Werfen: Speakers Bureau; Sobi: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau. Key:Novo Nordisk: Other: Chair of Grants Committee; Takeda: Research Funding; Grifols: Research Funding; Uniqure: Consultancy. Miesbach:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioMarin Pharmaceutical Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; UniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Recht:Spark: Research Funding; Novo Nordisk: Consultancy, Other: personal fees, Research Funding; uniQure: Consultancy, Other: personal fees, Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; BioMarin: Research Funding; Pfizer: Consultancy, Other: personal fees; Genentech: Consultancy, Other: personal fees, Research Funding; CSL Behring: Consultancy, Other: personal fees. Gomez:Global Blood Therapeutics: Speakers Bureau. Gut:uniQure: Current Employment. Pipe:Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy. OffLabel Disclosure: Etranacogene dezaparvovec (AMT-061) is an investigational gene therapy for hemophilia B comprising an adeno associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with liver specific promoter.

Introduction Haemophilia is characterized by frequent haemarthrosis, leading to acute/chronic joint pain. Aim To assess self-reported prevalence, description and management of pain in adult males with mild-to-severe haemophilia and history of joint pain/bleeding. Methods Participants completed a pain survey and five patient-reported outcome instruments assessing pain, functional impairment and health-related quality of life (HRQoL). Results Of 381 participants enrolled, median age was 34 years; 77% had haemophilia A, 71% had severe disease and 65% were overweight/obese. Many (56%) were not receiving routine infusions; 30% never received routine infusions. During the prior 6 months, 20% experienced acute pain, 34% chronic pain and 32% both acute/chronic pain. Subjects with both acute/chronic pain (vs. none, acute or chronic) were more likely to be depressed (30% vs. 0–15%), obese (35% vs. 20–29%) and have lower HRQoL (mean EQ-5D visual analog scale, 69 vs. 83–86) and function (median overall Hemophilia Activities List, 60 vs. 88–99). Most common analgesics used for acute/chronic pain during the prior 6 months were acetaminophen (62%/55%) and non-steroidal anti-inflammatory drugs (34%/49%); most common non-pharmacologic strategies were ice (65%/33%) and rest (51%/33%). Hydrocodone-acetaminophen was the most common opioid for both acute/chronic pain (30%); other long-acting opioids were infrequently used specifically for chronic but not acute pain (morphine, 7%; methadone, 6%; fentanyl patch, 2%). Conclusion Patients with chronic pain, particularly those with both acute/chronic pain, frequently experience psychological issues, functional disability and reduced HRQoL. Treatment strategies for acute pain (e.g. routine infusions to prevent bleeding) and for chronic pain (e.g. long-acting opioids) may be underused.

Objectives There is limited understanding of the effects of bleeding episodes on the daily lives of patients with congenital hemophilia with inhibitors and their caregivers. This analysis of the Dosing Observational Study in Hemophilia examined the impact of acute bleeding episodes on work, school, and family activities. Methods Patients and caregivers participated in a diary study for 90 or more days or until patients experienced four bleeding episodes. All bleed treatments, interference with daily activities, and quality-of-life assessments were captured in daily records. Patients and caregivers reported planned workdays or school days eligible to be "lost" so as to differentiate from days lost because of disability or nonworking status, weekends, and vacations. Results Diaries were completed for 39 patients (18 adults and 21 children). Bleeding episodes that continued for 3 or more days (16.4%) accounted for most of the major changes to family plans. For the 38 patients with bleeding episodes, 47% of 491 bleed days fell on planned workdays or school days; the remainder fell on weekends, holidays, or nonworkdays or non–school days and therefore did not count as "lost days." Patients reported a loss of productivity on a greater percentage of eligible bleed days than did caregivers (3.9% vs. 0.8%, respectively). Patients and caregivers reported 13.5%/9.3% fully missed and 3.5%/7.6% partially missed days. Conclusions This study demonstrated that in hemophilia with inhibitors, bleeding episodes interfere with the daily activities of patients and their caregivers. Furthermore, documenting only lost days underestimated the impact of bleeding episodes because of the high percentage of days without planned work or school.

Background: Gene therapy for hemophilia offers the possibility of ameliorating the disease severity to a milder or functionally curative state through a single treatment. AMT-061 is an investigational gene therapy for hemophilia B comprising an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with liver-specific promoter. Aims: Confirm that a single dose of AMT-061 will provide a minimum-therapeutic response of FIX activity 6-weeks post-dose in participants with severe or moderate-severe hemophilia B. Here, 1 year of follow-up will be presented for the first time. Methods: Phase 2b, open-label, multi-center trial (NCT03489291) in adult males with FIX ≤2% and without active hepatitis or uncontrolled HIV. Participants were not excluded based on neutralizing antibodies to AAV5. Participants received a single intravenous dose of AMT-061 (2x1013 gc/kg) and will be followed for 5-years. The primary endpoint was FIX activity at Week 6. Secondary endpoints include e-diary recordings of bleeds and FIX concentrate use, laboratory parameters, joint health, patient-reported outcomes, and adverse events (AEs). Results: All participants had FIX ≤1% (severe or moderately-severe FIX deficiency), required routine FIX prophylaxis, and had neutralizing activity to AAV5 at baseline. Following AMT-061 treatment, FIX activity increased rapidly (Figure) to a mean of 31% at Week 6. At Week 36, mean FIX activity increased further to 45% with FIX activity levels of 54%, 30% and 51% in participants 1-3 respectively. As of 36 weeks, there were no bleeds post-treatment and no requirement for FIX replacement aside from protocol-specified use for perioperative management in participant 3. There were no clinically significant elevations in liver enzymes and no participants required steroids related to the treatment. One participant experienced 2 mild AEs possibly related to treatment shortly after dosing (self-limiting headache and slightly elevated CRP). One patient had hip surgery due to worsening of pre-existing avascular necrosis deemed unrelated by investigator to AMT-061 and received FIX per protocol according to standard clinical practice. No participant developed inhibitors to FIX. Updated results to 52 weeks of follow-up will be presented. Conclusions: Sustained elevation of FIX activity into the mild-to-normative range were observed in all participants 36 weeks after treatment with AMT-061. AMT-061 was safe and well-tolerated with no requirement for immunosuppression. These data support the ongoing Phase 3 study. Figure Disclosures Pipe: Novo Nordisk: Consultancy; Apcintex: Consultancy; Roche/Genentech: Consultancy; BioMarin: Consultancy; Shire: Consultancy; Sanofi: Consultancy; uniQure: Consultancy; Pfizer: Consultancy; HEMA Biologics: Consultancy; Catalyst Bioscience: Consultancy; Freeline: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; Spark Therapeutics: Consultancy. Giermasz:Genentech/Roche: Consultancy, Other: Research, Speakers Bureau; Sangamo: Other: Research; BioMarin: Consultancy, Other: Research; uniQure: Consultancy, Other: Research; Bioverativ/Sanofi: Consultancy, Speakers Bureau. Castaman:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Key:Uniqure BV: Research Funding. Leebeek:CSL Behring: Research Funding; Baxalta/Shire: Research Funding; uniQure BV: Consultancy, Research Funding. Miesbach:Bayer, Chugai, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire, UniQure: Speakers Bureau; Bayer, BioMarin, CSL Behring, Chugai, Freeline, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda/Shire, UniQure: Consultancy; Bayer, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire: Research Funding. Recht:Bioverativ, CSL Behring, Genentech, Kedrion, NovoNordisk, Pfizer, Shire, Uniqure: Consultancy; American Thorombosis & Hemostasis Network: Other: Immediate Past Chair; Bioverativ, Genentech, NovoNordisk Shire: Research Funding. Gomez:Alnylam: Consultancy; Novo Nordisk, Novartis, Pfizer, Sanofi, Takeda, UniQure: Research Funding. Long:Uniqure BV: Employment. Gut:Uniqure BV: Employment. von Drygalski:University of California San Diego: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UniQure, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Founder.

Introduction Current adeno-associated viral (AAV) vector-based gene therapy strategies for hemophilia rely on systemic administration of the vector. Durable expression of the transgene over the span of years has been reported from several trials, yet information on the clearance of vector material from bodily fluids is still limited and monitoring of "shedding" is required during trials despite lack of evidence of environmental or transmission risk. Here, we examined the magnitude and duration of the presence of vector DNA in participants from a Phase I/II study of an AAV5-hFIX wildtype construct (AMT-060; NCT02396342) and from a Phase IIb study utilizing the enhanced version, AAV5-hFIX Padua (AMT-061; NCT03489291). Methods Adult male participants with severe or moderately severe hemophilia B received a single intravenous infusion of either AMT-060 at 5x1012 genome copies(gc)/kg (low dose) or 2×1013 gc/kg (high dose), or AMT-061 at 2x1013gc/kg in one of two ongoing trials. Assessments in both trials included efficacy and safety outcomes as well as vector shedding in whole blood and semen. Vector shedding was also measured in nasal secretions, feces, urine, and saliva in participants receiving AMT-060. Vector shedding was analyzed using a validated quantitative real time polymerase chain reaction (qPCR) based assay measuring presence of vector DNA in the bodily fluids. Vector clearance was reached when vector DNA was either zero or below the limit of detection (LOD) for three consecutive measurements. The range in time to the first and the third consecutive negative measurement for each dose group are provided. Results Treatment with AMT-060 resulted in sustained improvement in FIX activity for up to 3.5 years [Mean FIX activity was 5.1% (low dose group at 3.5 years) and 7.5% (high dose group at 3 years)] and treatment with AMT-061 resulted in mean FIX activity of 45% over 36 weeks. AMT-060 and AMT-061 reduced the mean number of annualized bleeds by between 82% and 100% respectively. AMT-060 reduced the requirement for exogenous FIX administration by 86% and was abrogated with AMT-061. Both AAV5-hFIX and AAV5-hFIX Padua were safe and well tolerated and no unexpected TRAEs have been observed with longer-term follow up. Table 1 describes the time in weeks to the first and last of three consecutive measures of vector DNA of either zero or Conclusions Post-AMT-060 treatment, vector DNA was undetectable in all participants in the high dose group by 10 months and considered cleared by 16 months in all bodily fluids except blood. AMT-060 was cleared from the blood in 100% of participants in the low dose group at 3 years and 80% of participants in the high dose group by 2.5 years. As expected, AMT-061 vector DNA was detectable at 36 weeks in blood and in the semen of 1 of 3 participants, although clearance had not yet been established in the remaining participants. The presence of vector DNA in bodily fluids assessed was not associated with any adverse safety or efficacy findings. Disclosures Sawyer: Uniqure BV: Employment. Gielen:uniQure Biopharma: Employment. Twisk:uniQure Biopharma: Employment. Long:Uniqure BV: Employment. Gut:Uniqure BV: Employment.

IntroductionQuality-of-life (QOL) assessments in frequently bleeding patients with congenital hemophilia with inhibitors and their families are confounded by preexisting arthropathy and family circumstances. Periodic QOL assessments typically made on nonbleed days may not provide complete reflections of the burden on patients/families.AimTo evaluate the impact of bleeding episodes on patients/caregivers/families and the association between monthly QOL scores and patients' average diary experiences.MethodsFrequently bleeding inhibitor patients (≥four bleeds in 3 months), or their caregivers, provided daily assessment of EuroQol five-dimensional questionnaire and EuroQol five-dimensional questionnaire visual analogue scale, pain (11-point Likert scale), and family anxiety/stress/activity change over 3 to 6 months. QOL scores were stratified by bleed/nonbleed days.ResultsPatient QOL assessments were recorded by 37 of the 39 enrolled patients/caregivers (3771 of 3777 eligible dairy days, 472 bleed/3299 nonbleed days). Median (range) diary duration was 91 (66–180) days, with 8.2% (0%–72.2%) bleed days. Mean health scores were significantly worse on bleed days than on nonbleed days (P < 0.0001 for all): EuroQol five-dimensional questionnaire index, 0.66 versus 0.82; visual analogue scale health, 69.7 versus 77.4; and pain score, 4.1 versus 1.8. Bleed days also had higher (P < 0.001) proportions of days with abnormalities in family anxiety/stress (42% vs. 30%) and family activity changes (34% vs. 21%).ConclusionsAssessing the impact of hemophilia with inhibitors on patient/family QOL typically includes periodic (likely nonbleed day) evaluations reflecting baseline abnormalities. Daily assessment, however, indicated that frequent acute bleeds impair QOL beyond patient's nonbleed day baseline. New approaches are required to assess the cumulative impact of frequent acute bleeds on patients and their families.

Patients with congenital haemophilia with inhibitors experience acute bleeds managed with bypassing agents, such as recombinant FVIIa (rFVIIa). Home-based treatment and dosing patterns in the US remain poorly described. This study aimed to assess the prescribed and actual rFVIIa dosing in frequently bleeding inhibitor patients (≥4 bleeds in 3 months) prescribed first-line therapy with rFVIIa. Patients or caregivers recorded daily diaries, including the details of all bypassing agent infusions for 3-6 months. Median (range) initial rFVIIa dose prescribed for joint, muscle and other bleeds was 167.5 (61.0-289.0) mcg kg(-1). Additional rFVIIa doses prescribed were 90 (61-270) mcg kg(-1) at an interval of 2.5-3 (1-24) h. The actual initial rFVIIa dose reported by patients/caregivers for 158 bleeds was 212 (59-400) mcg kg(-1), with total dose per episode of 695 (74-21257) mcg kg(-1). Patient/caregiver-reported average dose per bleed was 146 (40-400) mcg kg(-1) across 5 (1-106) infusions. The initial rFVIIa dose was higher for haemarthrosis (223 [59-400] mcg kg(-1)) than muscle bleeds (148 [74-300] mcg kg(-1); P = 0.07). Initial and mean dose per day changed as treatment progressed. The DOSE study indicates that frequently bleeding inhibitor patients are prescribed and use higher rFVIIa dosing for all bleed types than recommended in the package insert (90 mcg kg(-1)). The rFVIIa dosing was highly variable within and across bleed types, with higher initial doses used for joint bleeds than muscle and other bleed types, particularly in the first days of treatment. This suggests that patients/caregivers have adopted home treatment strategies based on physician discretion and individual responses and experience.

Background/Aims: To assess height standard deviation scores (HSDS) in patients with Turner syndrome (TS) by age at treatment initiation and varying durations of treatment with growth hormone (GH). Methods: GH treatment-naïve patients with TS from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® Registry were analyzed at baseline, 4 months, and annually. Results: Three hundred and eighty-two patients with TS had a baseline mean (±SD) HSDS of –2.6 ± 0.9. Patients received short-term (1 year), long-term (–2. Patients starting GH at a younger age experienced better growth response, regardless of treatment duration. Change in HSDS from baseline (ΔHSDS) at 4 months correlated positively with ΔHSDS at 1 and 3 years, and ΔHSDS at 1 year with ΔHSDS at 3 years (p values from 0.0017 toConclusions: Height gains in patients with TS during short-term treatment were found to be highly predictive of longer-term results. Continuation of GH treatment (≧3 years) resulted in 62.3% of the patients achieving an HSDS within the normal population range, indicating the clinical importance of early initiation and continuation of GH treatment in patients with TS.

To evaluate the efficacy of ultra-low-dose 10-microgram 17beta-estradiol (E2) vaginal tablets for treatment of vaginal atrophy.Postmenopausal women (N=309) were randomly assigned to 10-microgram E2 or placebo vaginal tablets for 52 weeks in a multicenter, double-blind study. Primary efficacy endpoints included change from baseline to week 12 in vaginal cytology, vaginal pH, and most bothersome urogenital symptoms score. Grading of vaginal health was a secondary efficacy assessment. Safety assessments included endometrial biopsy, physical and gynecologic examinations, and recording adverse events.At week 12, the change from baseline for 10 micrograms E2 compared with placebo demonstrated significant improvement in vaginal Maturation Index (proportion of parabasal cells: -37% compared with -9%; superficial cells: 13% compared with 4%; intermediate cells: 24% compared with 5%; P.001 for each), Maturation Value (25.0 compared with 6.5, P.001), grading of vaginal health (-0.91 compared with -0.51, P.001), vaginal pH grade (-1.3 compared with -0.4, P.001), and most bothersome symptoms score (-1.23 compared with -0.87, P=.003). For each component of vaginal Maturation Index, vaginal Maturation Value, grading of vaginal health, and vaginal pH, treatment effects were statistically different from placebo after 2 weeks of treatment. For most bothersome symptoms, treatment effect became apparent after 4 weeks and reached statistical significance at week 8 of therapy. All treatment effects were statistically significant at week 52. There were no major safety findings regarding physical, gynecologic, or laboratory assessments.After 12 weeks of treatment, an ultra-low-dose 10-microgram E2 vaginal tablet, compared with placebo, demonstrated significant improvement for the primary endpoints: vaginal cytology and pH and most bothersome urogenital symptoms score.ClinicalTrials.gov, http://clinicaltrials.gov, NCT00108849I.

Introduction Acquired haemophilia (AH) is a rare disorder caused by autoantibodies against factor VIII. Aim The Hemostasis & Thrombosis Research Society (HTRS) Registry was used to monitor the safety of recombinant FVII (rFVIIa). This study aims to report data from the HTRS Registry regarding safety and efficacy of rFVIIa for haemostatic management of surgeries and other invasive procedures in patients with AH. Methods For each rFVIIa-treated procedure, the initial dose, total dose, average infused dose, number of doses and treatment duration were calculated. Efficacy was assessed on a 4-point scale. Results Of 166 registered patients with AH, 37 patients underwent 58 procedures [30 (51%) rFVIIa-treated]. The median (range) age of all patients undergoing procedures was 70 (13–93) years; for rFVIIa-treated patients, 74 (28–89) years. Approximately 67% (39/58) of all procedures were elective. Overall, the most common procedures were endoscopy (12) and central venous access device (10); rFVIIa was used preoperatively (11), postoperatively (13) and during six follow-up procedures during ongoing postoperative rFVIIa treatment. The median (range) initial dose was 90.0 (44–187) μg kg−1 preoperatively and 106.0 (56–270) μg kg−1 postoperatively. For rFVIIa-treated episodes with a reported outcome, 20 (91%) were rated excellent/good or no additional agents used and 2 (9%) were rated as poor/ineffective requiring a switch to another bypassing agent. No thromboembolic events were reported. Conclusions Adequate haemostasis was provided for 91% of rFVIIa-treated procedures at doses largely conforming to the package insert. No safety concerns were reported.

This study aimed to assess attainment of genetic height potential after long-term growth hormone (GH) treatment in GH-naïve children diagnosed with isolated growth hormone deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), born small for gestational age (SGA), or idiopathic short stature (ISS) enrolled in the American Norditropin®Web-enabled Research (ANSWER) Program.Children with IGHD (n=2884), MPHD (n=200), SGA (n=481), or ISS (n=733) with baseline height standard deviation score (HSDS)≤-2 were assessed over 5 years of GH treatment for mean HSDS, change in HSDS (ΔHSDS), and corrected HSDS (HSDS-target HSDS).Mean HSDS and corrected HSDS significantly increased to close to target height across all diagnostic groups after 5 years of GH treatment (P0.0001). ∆HSDS at year 5 increased for all groups (IGHD: 1.8; MPHD: 2.1; SGA: 1.8; ISS: 1.6). Among patients who continued GH for 5 years, mean insulin-like growth factor-I (IGF-I) SDS increased to within normal range across all groups. Body mass index (BMI) SDS remained relatively stable in all diagnostic groups. Bone age (BA) increased, and the mean BA to chronological age (BA/CA) ratio reached or approached 1 across diagnostic groups over 5 years of GH treatment.Long-term GH therapy resulted in a significant increase in mean HSDS and corrected HSDS from baseline values in all diagnostic groups. The observed increase in mean corrected HSDS is consistent with growth that approached the patients' genetic height potential, although complete height gains will be evaluated at the attainment of final height.

Dear editor Acquired hemophilia (AH) is a rare (incidence is 1 per 1.5 million) but often severe bleeding disorder characterized by autoantibodies to coagulation factor VIII (FVIII). It is associated with life-threatening bleeding and ~20% mortality.1,2 Recombinant factor VIIa (rFVIIa; NovoSeven® RT, Novo Nordisk A/S, Bagsvaerd, Denmark) received an indication from the US Food and Drug Administration (FDA) in October 2006 for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in patients with AH.3 The approval of rFVIIa for AH was supported by data collected through the Hemostasis and Thrombosis Research Society (HTRS) Registry since the product’s original approval in 1999. The HTRS Registry is a longitudinal US database created by the Society in collaboration with Novo Nordisk to study treatment strategies for patients with bleeding disorders and to provide post-marketing surveillance. It was adapted in 2006 to fulfill a 5-year commitment by Novo Nordisk to the FDA to provide surveillance around AH. AH affects only about 350 patients per year in the US and many patients are treated outside of the federally designated and funded hemophilia treatment center (HTC) network by hematologists, hematologist/oncologists, and other hospital-based physicians. Many hospitals and most of the ~140 HTCs do not frequently see patients with this disorder, or else see them so rarely that maintaining active IRB renewals and trained staff to participate in the HTRS Registry over 5 years would be considered burdensome. In addition, requests for consultation on such patients from those who first see the patients (emergency medicine, hospitalists, critical care, obstetrics/gynecology, rheumatology) may originate within the hematology staff at any hospital and may be limited to phone consultation with a remote hematologist, thus limiting the amount of data available to the hematologist regarding patient treatment and outcomes. The objective of the Acquired Hemophilia Surveillance (AHS) project was to implement a simple IRB-exempt case report surveillance system to document the at-risk population exposed to rFVIIa and to capture data on the incidence of adverse events (AEs), particularly thromboembolic events (TEs) in these patients. It was specifically targeted to healthcare professionals (HCPs), including non-hematologists who did not belong to HTRS or who were based at HTCs that were resource constrained from considering HTRS participation. This AHS system was launched in April 2008 as a one-page fax-in reporting system maintained by Novo Nordisk. In June 2008, it was converted to a secured web-based platform located at novosevensurveillance.com by Outcome Sciences (Cambridge, MA, USA), a third-party contract research organization that also entered the preliminary faxed-in reports and maintained the database. The AHS web portal allowed for simple electronic entry of demographic and treatment information on acquired hemophilia cases, with the addition of a full safety report form where applicable. AHS takes advantage of the HIPAA exclusion for collection of safety information (45 CFR §164.512(b)(iii)(D)). Reporting HCPs were provided fair market compensation per case entry. Field-based medical liaisons were integrally involved in obtaining information about potential AH cases from visits to HTC and non-HTC sites where they discussed both the HTRS Registry (primary goal) and the AHS project (secondary goal) with HCPs as a means of contributing AH information for post-marketing safety. Medical liaisons distributed copies of a “dear doctor” letter describing the AH post-marketing safety requirement and the AHS project, magnets with the HTRS and AHS project contact numbers, and other supporting materials. Bleed data collected from AHS between April 2008 and 30 November 2011 were analyzed for the safety of rFVIIa treatment in patients with AH. Information on demographics, rFVIIa dosing (entered via an optional free text field) and incidence of thrombotic events was collected and reported using descriptive statistics. Reporting HCPs were required to complete an affirmation about presence/absence of adverse events, and if reporting adverse events to complete a detailed safety information form consistent with the data required to complete a standard MedWatch report. From April 2008 through 30 November 2011, 38 individual HCPs submitted 99 case reports (including 65 treated with rFVIIa) via facsimile or electronic data capture interface. The reports were from both HTCs (44) and non-HTCs (48), and more commonly from centers that did not participate in HTRS (84) than did participate (8). Of the 99 patients, 41 (41%) were male and 58 (59%) were female. The mean age was 66.6 years (range 16.4 to 97.3 years). The most common underlying conditions were autoimmune (34 patients), malignancy (12 patients), and post-partum (5 patients). The mean (SD) anti-VIII titer was 154.5 (453.7) Bethesda units (BU) and the median (range) anti-VIII titer was 35 (1–3,789) BU. Factor VIII levels were reported for 93 of the 99 patients. Fifty-eight percent (57/99) of the subjects had reported factor VIII levels ≤1%. The mean (median) factor VIII level in 36 remaining patients (≥1% FVIII levels) was 8.1% (4.0%) with a range of 1.8%–50%. The mean (median) reported discrete bleeding episodes per patient was 4.3 (2.0) with a range of 0–100 episodes since the time of AH diagnosis. Most of these episodes were spontaneous (84 patients), surgical (14 patients), or related to a procedure (12 patients). Details on specific bleeding episodes were not captured in this brief report format. The use of rFVIIa was indicated in 65 case reports (83%), including 50 first-line treated cases (77%), 14 second-line treated cases (22%), and one with unspecified line of treatment. A bypassing agent other than rFVIIa was indicated to have been used in 13 case reports (17%). No bypassing agent was indicated to have been used in 21 case reports. The acquired hemophilia condition was reported to have been resolved in 51 cases (52%) and not resolved in 30 cases (30%). Resolution was reported as “unsure” in 17 cases and not reported for one case. The mean (median) time to acquired hemophilia resolution was 7.5 (2.0) months with a range of 1–52 months. There were five reported deaths. There were 13 cases for which the mortality status was reported as “unsure.” In the 65 cases where rFVIIa was used, the reporters affirmed that none of the patients suffered an adverse event that was considered possibly/probably related to rFVIIa. Therefore, there was no detailed treatment and outcome information requested or provided on adverse events. Reports of dosing as a write-in field, most with limited detail, suggest that full treatment records were not available or reviewed during the preparation of many of these reports, and some patients might have been treated at facilities outside the reporting sites. Since many of the reports also reflect that patients experienced multiple episodes (mean 4.3 per patient), the interpretation of general information provided in response to a single question on efficacy at 24 and 72 hours remains unclear. Among the 50 patients who received rFVIIa as first-line treatment and had outcomes reported, 47 and 46 were reported to have “excellent/good” or “fair/partially effective” outcome at 24 and 72 hours. Among the 14 patients who received rFVIIa as second-line treatment and had outcomes reported, 12 were reported to have an “excellent/good” or “fair/partially effective” outcome at 24 and 72 hours. For rare disorders or rare complications of common disorders, the standard post-marketing surveillance approach of an IRB-approved observational or product registry may have significant limitations and barriers at the site-implementation level. AHS provides an innovative approach to augment data from formal post-marketing registries under a HIPAA exclusion for HTCs, hematology/oncology practices, and even primary hospital-based treating physicians/pharmacists (emergency room, intensive care unit, post-partum unit) to capture basic surveillance data for AH patients exposed to rFVIIa. AHS was not designed to provide registry-level data, but rather to capture 25% to 50% of identified case reports where registry data entry would not occur. Medical liaisons can play an important role in the identification of patients with rare disorders or complications and can provide information about the primary PMS registry and/or backup systems. The AHS project reaffirms the safety of rFVIIa and the low rate of thrombotic complications. However, AHS lacks the detailed information available through traditional research registries at large centers, such as data on individual bleeds, treatment of individual bleeding episodes, rFVIIa dosing, time to hemostasis, and the relationship of immunosuppressive treatments to AH resolution.

Recombinant activated factor VII (rFVIIa) is indicated for treatment of bleeding in congenital haemophilia with inhibitors (CHwI) using 90 μg kg(-1) every 2-3 h (EU and US) or a single 270 μg kg(-1) dose (EU only) with ~90% efficacy reported for both regimens. Dosing of rFVIIa varies, and home treatment makes assessment of frequency of doses >90 μg kg(-1), the intervals before additional treatment, and the risk for thromboembolic events (TEs) more difficult. This post hoc analysis assessed the safety and distribution of rFVIIa dosing in CHwI and the impact of >240 μg kg(-1) dosing on subsequent bypassing agent (BPA) dosing interval and frequency. Data regarding on-demand or prophylactic rFVIIa dosing, TE incidence and subsequent BPA dosing after high rFVIIa doses were compiled from multiple sources incorporating safety surveillance. A total of 61 734 rFVIIa doses were reported in 481 patients treated for 3947 bleeds and for 43 135 prophylaxis days. Over half (52%) exceeded 120 μg kg(-1), 37% exceeded 160 μg kg(-1) and 15% exceeded 240 μg kg(-1). Subsequent doses of BPA(s) were administered after 38% of initial and 49% of any rFVIIa dose >240 μg kg(-1), and were most frequently administered ≥24 h after initial (40%) or any (53%) doses >240 μg kg(-1). No TEs were reported. The findings of this analysis show that rFVIIa doses >90 μg kg(-1) are utilized for 'real-world' treatment of children and adults. When additional BPA was administered following an rFVIIa dose >240 μg kg(-1), reported intervals were prolonged, often ≥24 h. No safety issues were identified in the 61,734 doses analysed.

Guy Young,1 Caitlyn T Solem,2,3 Kate Hoffman,4 Jenna Kabawat,4 A Simon Pickard,3 Robert Z Gut,5 David L Cooper51Children's Center for Cancer and Blood Disorders, Children's Hospital Los Angeles, Los Angeles, CA, 2Pharmerit, Bethesda, MD, 3Center for Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, IL, 4Outcome Sciences, Cambridge, MA, 5Novo Nordisk Inc, Princeton, NJ, USAObjective: The daily recordings of treatment by patients with congenital hemophilia with inhibitors and their caregivers were assessed as part of the Dosing Observational Study in Hemophilia (DOSE) to understand the patterns of bypassing agent use and health-related quality of life.Methods: Frequently bleeding patients prescribed recombinant activated factor VII as first-line therapy were eligible. Participants recorded daily paper diaries for at least 90 days and until at least four bleeding episodes had occurred. Web-based entry was optional. Assessment included bleeding status, work or school day status, bleeding episode, treatment, impact on planned activities, and health-related quality of life.Results: Diaries were completed by 18 adults and 19 caregivers (21 children). A total of 4063 diary days and 194 bleeding episodes over 491 bleed days were recorded. A small proportion of diary days were bleed days (8.2%) or treatment days (8.2%). Half the bleed days were not planned work or school days for patients (53%) or caregivers (48%). An exact agreement was observed between electronic and paper records for 93% of the reviewed health-related quality of life measurements.Conclusion: Daily diary completion by patients and caregivers is feasible and provides insight into the impact of congenital hemophilia with inhibitors on daily activities and overall quality of life. Positive participation and completion rates were supported by frequent patient contact made by independent patient support liaison personnel.Keywords: daily assessment, recombinant activated factor VII, rFVIIa, NovoSeven, quality of life

Background Noonan syndrome (NS) is a genetic disorder characterized by phenotypic features, including facial dysmorphology, cardiovascular anomalies, and short stature. Growth hormone (GH) has been approved by the United States Food and Drug Administration for short stature in children with NS. The objective of this analysis was to assess the height standard deviation score (HSDS) and change in HSDS (ΔHSDS) for up to 4 years (Y4) of GH therapy in children with NS. Methods The American Norditropin Studies: Web-Enabled Research (ANSWER) Program®, a US-based registry, collects long-term efficacy and safety information on patients treated with Norditropin® (somatropin rDNA origin, Novo Nordisk A/S) at the discretion of participating physicians. A total of 120 children (90 boys, 30 girls) with NS, naïve to previous GH treatment, were included in this analysis. Results The mean (SD) baseline age of subjects (n = 120) was 9.2 (3.8) years. Mean (SD) HSDS increased from –2.65 (0.73) at baseline to –1.32 (1.11) at Y4 (n = 17). Subjects showed continued increase in HSDS from baseline to Y4 without significant differences between genders at Y1 or Y2. The mean (SD) GH dose was 47 (11) mcg/kg/day at baseline and 59 (16) mcg/kg/day at Y4. There was a negative correlation between baseline age and ΔHSDS at Y1 (R = –0.3156; P = 0.0055) and Y2 (R = –0.3394; P = 0.017). ΔHSDS at Y1 was significantly correlated with ΔHSDS at Y2 (n = 37; R = 0.8527, P Conclusions GH treatment-naïve patients with NS showed continued increases in HSDS during 4 years of treatment with GH with no significant differences between genders up to 2 years. Baseline age was negatively correlated with ΔHSDS at Y1 and Y2. Whether long-term therapy in NS results in continued increase in HSDS to adult height remains to be investigated. Trial registration ClinicalTrials.gov NCT01009905

Control of bleeding in patients with congenital haemophilia with inhibitors requires use of bypassing agents such as recombinant activated factor VII (rFVIIa). Due to the difficulties in performing prospective clinical trials in this small subgroup of patients with haemophilia and the need for postmarketing surveillance, a large-scale database was developed by the Hemophilia and Thrombosis Research Society. This report comprises an analysis of the database with respect to assessing dosing and efficacy of rFVIIa by bleed type and location. Between January 2004 and November 2008, data from 129 inhibitor patients with 2041 rFVIIa-treated bleeds were analysed. The bleeds were primarily spontaneous (58%) and traumatic (30%). The most common locations were joints (57%), muscle (20%), mucosal (7%) and subcutaneous (6%). Median total rFVIIa doses per bleeding episode for spontaneous and traumatic bleeds were 540 mcg kg(-1) (4 injections/2 days) and 300 mcg kg(-1) (2.5 injections/1 day) respectively. Median total rFVIIa dose (mean dose, number of injections) was 480 mcg kg(-1) (110 mcg kg(-1) , 3) for joint; 557 mcg kg(-1) (120 mcg kg(-1) , 4) for muscle; 360 mcg kg(-1) (120 mcg kg(-1) , 3) for mucosal and 402 mcg kg(-1) (117 mcg kg(-1) , 3) for subcutaneous. Overall efficacy ranged from 89% to 93%; bleeding stopped in 89% of spontaneous and 93% of traumatic bleeds, 90% of joint bleeds, and 89% of muscle, mucosal,and subcutaneous bleeds. Although spontaneous bleeds require slightly higher doses than traumatic bleeds, most bleeds were treated with a median of 3-4 injections (110-130 mcg kg(-1) ). Effectiveness of rFVIIa was consistently high across bleeding types and locations.

To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17β-estradiol vaginal tablets in postmenopausal women with vaginal atrophy.Endometrial biopsy data from individuals using active treatment (n=205) in a randomized, double-blind, placebo-controlled trial were pooled with the data from an open-label endometrial safety trial (n=336). Patients received 10-microgram estradiol vaginal tablets for 52 weeks. All endometrial biopsy samples were histologically analyzed at baseline and at end of trial by the same laboratory in both trials.A total of 541 women using estradiol were included in the combined analysis of endometrial safety. A total of 456 women completed the trials, and 443 women had a biopsy performed at week 52: 85.6% were categorized as "atrophic endometrium," 12.6% had nonevaluable biopsy samples, 1.1% had polyps, and 0.2% were categorized as "weakly proliferative." One case of complex hyperplasia without atypia was reported in an individual exposed to trial drug for only 9 days. One woman's biopsy sample demonstrated endometrioid adenocarcinoma, grade 2, but the lack of an evaluable screening biopsy sample makes it uncertain whether the carcinoma was preexisting. In total, two events of hyperplasia and carcinoma were reported in 386 evaluable biopsy samples (incidence rate 0.52% per year).The reported background incidence rate of endometrial hyperplasia and carcinoma in postmenopausal women is 0% to 1%. The results of this pooled analysis therefore support the endometrial safety of unopposed ultra-low-dose vaginal estrogen. There was no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women undergoing treatment with 10-microgram estradiol vaginal tablets for 1 year under study conditions.ClinicalTrials.gov, www.clinicaltrials.gov, NCT00108849 (VAG-2195) and NCT00431132 (VAG 1748).II.

To assess gender-, pubertal-, age-related differences in change from baseline height standard deviation score (), data from 5,797 growth hormone (GH) naïve pediatric patients ( at year 1 was significantly greater for males versus females (), but no other gender differences were observed. For patients with GHD, was greater in prepubertal than in pubertal patients. Younger patients for both genders ( ( for GHD, MPHD, and ISS). Overall, positive were observed in all patients, with greater growth responses in younger prepubertal children, emphasizing the importance of starting GH treatment early.

To evaluate the efficacy of two vaginal doses of estradiol (E2) compared with placebo in the treatment of atrophic vaginitis.In a multi-center, randomized, double-blind, parallel-group study, 230 postmenopausal women received treatment with 25 mcg or 10 mcg E2 or placebo for 12 weeks. Efficacy was measured through composite score of three vaginal symptoms and grading of vaginal health. Additional analyses included maturation of vaginal and urethral mucosa. Safety assessments included endometrial biopsy, adverse events, changes in laboratory tests, and physical examinations. After 12 weeks of treatment, all patients were switched to the open-label extension and received treatment with 25 mcg E2 up to week 52.Vaginal tablets with 25 mcg and 10 mcg E2 showed significant (P.001) improvement in composite score of vaginal health. Other results with 10 mcg E2 were not entirely consistent with those for 25 mcg E2. Over 12 weeks, both active treatments resulted in greater decreases in vaginal pH than placebo. There were no significant differences between the 25 mcg and 10 mcg E2 groups in terms of improvements in maturation value or composite score of three vaginal symptoms. The efficacy was maintained to week 52 with 25 mcg E2.Vaginal tablets with 25 mcg and 10 mcg E2 provided relief of vaginal symptoms, improved urogenital atrophy, decreased vaginal pH, and increased maturation of the vaginal and urethral epithelium. Those improvements were greater with 25 mcg than with 10 mcg E2. Both doses were effective in the treatment of atrophic vaginitis.ClinicalTrials.gov, www.clinicaltrials.gov, NCT00465192 and NCT00464971I.

Abstract 3371 Background: Acquired hemophilia (AH) is a rare (1 per 1.5 million), life-threatening autoimmune disorder characterized by autoantibodies to coagulation factor VIII (FVIII). It is associated with life-threatening bleeding and ≈20% mortality. Following approval of recombinant factor VIIa (rFVIIa) by the FDA in 2006 for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in patients with AH, Novo Nordisk agreed to monitor treatment through the IRB-approved Hemostasis and Thrombosis Research Society (HTRS) research registry, although this proved impractical outside of existing registry sites and hemophilia treatment centers (HTCs). Therefore, the Acquired Hemophilia Surveillance (AHS) Project was developed as a web-based, IRB-exempt method to collect additional rFVIIa safety data, and particularly assess for thromboembolic events (TEs) in these generally older patients. Methods: The AHS project was launched in April 2008 as a one page fax-in reporting system and in June 2008 converted to a web-based platform located at novosevensurveillance.com. AHS takes advantage of the HIPAA exclusion for collection of safety information (45 CFR μ164.512(b)(iii)(D)). Reporting HCPs were provided fair market compensation per case entry. Information on demographics, rFVIIa dosing (entered via an optional free text field) and incidence of thrombotic events was collected and reported using descriptive statistics through project completion in 2011. Results: From April 2008 through November 2011, 38 individual health care professionals submitted 99 case reports (including 65 treated with rFVIIa) via facsimile or electronic data capture interface. The reports were from both HTCs (44) and non-HTCs (48), and more commonly from centers that did not participate in HTRS (84) than did participate (8). Of the 99 patients, 41 (41%) were male and 58 (59%) were female. The mean age was 66.6 years (range 16.4 to 97.3 years). The most common underlying conditions were autoimmune (34 patients), malignancy (12 patients), and post-partum (5 patients). The mean (SD) anti-VIII titer was 154.5 (453.7) Bethesda units (BU) and the median (range) anti-VIII titer was 35(1–3789) BU. Factor VIII levels were reported for 93 of the 99 patients. Fifty-eight percent (57/99) of the subjects had reported factor VIII levels ≤ 1%. The mean (median) factor VIII level in 36 remaining patients (>1% FVIII levels) was 8.1% (4.0%) with a range of 1.8–50%. There were reported to be a mean (median) of 4.3 (2.0) discrete bleeding episodes per patient (range 0–100 episodes). Most of these episodes were spontaneous (84 patients), surgical (14 patients), or related to a procedure (12 patients). Details on specific bleeding episodes were not captured in this brief report format. No bypassing agent was indicated to have been used in 21 case reports. The use of rFVIIa was indicated in 65 case reports (83%), including 50 first-line treated cases (77%), 14 second-line treated cases (22%), and 1 with unspecified line of treatment. A bypassing agent other than rFVIIa was indicated to have been used in 13 case reports (17%). AH was reported to have been resolved in 51 cases (52%) and not resolved in 30 cases (30%). The mean (median) time to AH resolution was 7.5 (2.0) months with a range of 1–52 months. There were 5 reported deaths. The reporters affirmed that none of the 99 cases suffered an adverse event that was considered possibly/probably related to rFVIIa. Conclusion: For rare disorders or rare complications of common disorders, the standard post-marketing surveillance approach of an IRB-approved observational or product registry may have significant limitations and barriers at the site implementation level. AHS provides an innovative approach for HTCs, hematology/oncology practices, and even critical care physicians/pharmacists to capture basic surveillance data for AH patients exposed to rFVIIa. The AHS project reaffirms the safety of rFVIIa and the low rate of thrombotic complications. However, AHS lacks the detailed information available through traditional research registries at large centers, such as data on individual bleeds, treatment of individual bleeding episodes, rFVIIa dosing, time to hemostasis, and the relationship of immunosuppressive treatments to AH resolution. Disclosures: Lentz: Novo Nordisk A/S: Consultancy, Investigator Other. Tandra:Novo Nordisk Inc.: Investigator Other. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

4624 Introduction: Acquired hemophilia (AH) is a rare disorder marked by the development of autoantibodies to factor VIII. Patients typically present with bleeding and a prolonged aPTT that does not correct with mixing with normal plasma. Recombinant factor VIIa (rFVIIa) is the only FDA approved bypassing agent for treatment of bleeding in AH. The Hemostasis and Thrombosis Research Society Registry was established as an IRB-monitored web-based platform with informed consent in 1999 to support the society's research needs and monitor rFVIIa use after its FDA approval. AH surveillance was initiated in October 2006. Methods: Data on bleeding episodes entered between January 2004-November 2011 were analyzed. For each rFVIIa-treated bleed, the initial dose, total dose, mean dose per infusion, number of doses, and treatment duration were calculated. Results: Of 166 registered AH patients, 110 had bleeding episodes reported. Of 237 bleeds, 17 (7%) occurred in patients aged ≤40, 54 (23%) in ages 41–60, and 166 (70%) with age >60. The most common sites were subcutaneous (40%), mucosal (32%), muscle (20%) and joint (11%). Subcutaneous bleeds were more commonly reported in females (55% vs. 40% males) and white patients (44% vs. 27% black). Mucosal bleeds were more common in black patients (49% vs. 25%) and muscle bleeds more common in white patients (14% vs. 23%). There were 139 (59%) rFVIIa-treated bleeds (89 rFVIIa alone, 50 rFVIIa plus other agents/blood components); 127 were treated with rFVIIa first-line. There were 75 episodes (43 patients) treated with other hemostatic agents or blood components only, 21 episodes (18 patients) recorded with no treatment for the episode, and 2 episodes (2 patients) with no treatment data recorded. For rFVIIa-treated episodes, 71 were in males and 68 females; 101 were Caucasian and 30 were black. Mean (median) age at bleeding was 67 (69) years. rFVIIa-treated bleeds were spontaneous (95), traumatic (30), surgical/procedure-related (7), dental (2) or other (4). Median (IQR) initial rFVIIa dose was 90 (88–100) mcg/kg, and average dose per injection was 90 (88–99). The total dose per episode was 334 (166–1383) mcg/kg administered as 3 (2–14) injections over 1 (0–2.75) day. Median (IQR) data for rFVIIa dosing by treatment sequence, bleed location and type is described below: | | First line n=127 | Second line n=12 | Subcutaneous n=52 | Mucosa n=45 | |:--------------------- | ---------------- | ---------------- | ----------------- | -------------- | | Initial dose (mcg/kg) | 90 (87–100) | 90 (87–100) | 90 (90–97) | 90 (87–100) | | Mean dose (mcg/kg) | 90 (88–99) | 90 (90–97) | 90 (90–97) | 90 (88–99) | | Total dose (mcg/kg) | 300 (119–1345) | 577 (275–3430) | 577 (275–3430) | 300 (119–1345) | | # doses | 3 (1–13.5) | 7 (3.5–25) | 7 (3.5–25) | 3 (1–13.5) | | Duration (days) | 1 (0–4) | 7.5 (0.8–13.5) | 1.5 (0.8–4.1) | 1 (0–2.5) | | | Spontaneous n=95 | Traumatic n=30 | Other Medical Procedures n=5 | Surgery n=3 | |:--------------------- | ---------------- | -------------- | ---------------------------- | ---------------- | | Initial dose (mcg/kg) | 90 (83–93) | 93.5 (90–101) | 96 (78–100) | 90 (90–105) | | Mean dose (mcg/kg) | 90 (85–92) | 91.4 (90–100) | 96 (78–100) | 109 (100–115) | | Total dose (mcg/kg) | 290 (110–1132) | 314 (180–1430) | 900 (810–1152) | 9600 (5520–9885) | | # doses | 3 (1–12) | 3.5 (2.0–14.8) | 9 (6–12) | 88 (50–101) | | Duration (days) | 1 (0–2.5) | 1 (0.2–2.0) | 2.3 (0–3) | 10 (6–10.5) | Efficacy of rFVIIa, physician-rated for each regimen, was reported as “bleeding stopped” in 117 (85%) episodes; “bleeding slowed” in 15 (11%) episodes (stopped with other agents in 3 episodes); “no improvement” in 5 (4%) episodes (no bleed stop date identified in 4, stopped with other agent in 1), and was not documented in 1. Considering only the 4 rFVIIa treatment failures where bleeding stopped after switching to another agent, overall rFVIIa efficacy was 97%. The only thromboembolic event was transient neurologic symptoms in a 31-year-old post-partum patient after 110 doses of 90 mcg/kg every 2 hours. The neurologist reported it most likely related to eclampsia and vasculitis. Conclusions: The HTRS registry final analysis represents the 2nd largest data set in AH. While subcutaneous bleeding as a first bleed location was uncommon outside of Caucasians, it represents the most common bleed location of recorded bleeds in all race/ethnicity groups. As this registry was originally intended in part to track the safety of rFVIIa, the proportion of bleeds treated with rFVIIa (59%) and associated data derived from those bleeds may be somewhat biased and selective. Nevertheless, they are certainly indicative that rapid and safe hemostasis can be achieved with rFVIIa in an aging population with AH where thrombogenicity is of concern. Disclosures: Ma: Novo Nordisk Inc.: Consultancy, Speakers Bureau. Kessler: Novo Nordisk: Consultancy, Research Funding. Fisher: Novo Nordisk Inc.: Employment. Gut: Novo Nordisk Inc.: Employment. Cooper: Novo Nordisk Inc.: Employment.

Abstract 3372 Background: AH is a rare disorder caused by autoantibodies against factor VIII (FVIII). Patients can present with peri-operative bleeding, and a prolonged aPTT that doesn't correct with 1:1 mixing after 2 hours (37°C). The Hemostasis and Thrombosis Research Society (HTRS) Registry was established to support the society's research needs and monitor the safety of recombinant activated factor VII (rFVIIa). In October 2006, the FDA approved rFVIIa for the treatment of bleeding and prevention of bleeding during surgery in AH at 70–90 mcg/kg every 2–3 hours. In 2007, a new case report form (CRF) for capturing information about surgeries was added. Methods: Data on treatment during surgical procedures was collected from the HTRS registry surgical CRF. For each rFVIIa-treated surgery, the initial dose, total dose per procedure (prior to and post surgery), average infused dose, number of doses, and treatment duration were calculated. Queries were issued to verify any procedures lacking treatment data or where treatment was listed as “none”. Efficacy was assessed on a 4 point scale and an investigator assessed adequacy of hemostasis on the “planned regimen” immediately and at 24 and 72 hours. Results: Of 166 registered AH patients, 36 patients underwent 58 surgeries. There were 24 (43%) rFVIIa-treated procedures (17 rFVIIa only). The mean (range) age of all patients undergoing surgery was 69 (14–89), and for rFVIIa-treated patients was 77.8 (28–89). rFVIIa-treated patients were mostly female (71%) and Caucasian (59%). Approximately 33% (19/58) of all surgeries were elective, including 54% (13/24) of rFVIIa-treated surgeries. The most common procedures overall were central line placement (12), endoscopy (12) and orthopedic (5). rFVIIa-treated surgeries included: central venous access (6), endoscopy (5), incision, drainage and grafting of hand hematomas (3), AVM embolization (2), orthopedic procedures (2) cholecystectomy (1), colon biopsy (1), catheter removal (1), exchange of prostate brachytherapy implant (1), venipuncture (1) and IVC filter placement (1). rFVIIa was used pre-op in 19 procedures and post-surgery in 15. In 9/24 procedures (8/24 pre-op), a single rFVIIa dose was used. Median (range) for rFVIIa treatment is described in the table below: rFVIIa efficacy was rated as excellent/good in 17 (77.3%), fair/partially effective in 2 (9.1%), and poor/ineffective in 3 (13.6%). For those rated fair/partially effective, one received only one pre-op rFVIIa dose of 75 mcg/kg with antifibrinolytics (no post-surgery treatment) and the other received 1 pre-op and 2 post-op rFVIIa 106 mcg/kg doses at 2 hour intervals with no other treatments. For those rated poor/ineffective, one received rFVIIa and PRBCs only, one received rFVIIa 81 mcg/kg initially every 4–6 hrs then plasma-derived activated prothrombin complex concentrate (pd-aPCC) then rFVIIa, and one had resolution of a neck hematoma with rFVIIa (subsequently switched to pd-aPCC) but could not maintain an airway and was transferred to hospice. No thromboembolic events were reported in rFVIIa-treated patients. Two patients underwent 6 follow-up procedures during ongoing post-op rFVIIa-treatment. Eleven patients used hemostatic agents other than rFVIIa in 12 surgical procedures. These included use of pd- aPCC in 5 cases (3 pre-op; 2 pre-op and post-op) and use of desmopressin in 2 cases, and recombinant FVIII in 3 cases. Blood products (FFP, PRBCs) were used post-op in 2 cases. Thirteen patients underwent 16 surgeries with no reported treatment. Conclusions: rFVIIa provided adequate hemostasis for almost all rFVIIa-treated AH surgeries at doses largely conforming to the package insert. There were no safety concerns and no thromboembolic complications reported in this population of older patients. Lack of hemostatic therapy reported for some procedures may reflect surgery as a presenting AH symptom, surgery during ongoing treatment not requiring additional treatment, or surgery performed following immune suppression/tolerization. Disclosures: Ma: Novo Nordisk Inc.: Consultancy, Speakers Bureau. Kessler:Novo Nordisk: Consultancy, Research Funding. Fisher:Novo Nordisk Inc.: Employment. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Abstract 3316 Objective: Recombinant FVIIa (rFVIIa) is indicated for the treatment of bleeding episodes in hemophilia patients with inhibitors at a dose of 90 mcg/kg every 2–3 hours, or as a single 270 mcg/kg rFVIIa dose (outside US). As patient response and bleeds are variable, treatment is often individualized by the center and by the patient/caregiver administering rFVIIa. With home treatment, it is difficult to ascertain how often patients use higher doses (>90 mcg/kg), and whether these doses are associated with increased risk of thromboembolic events (TEs). The aim of this analysis was to understand the safety of higher rFVIIa doses and the intervals to subsequent doses. Methods: Data for rFVIIa on-demand (OD) bleed treatment in inhibitor patients were obtained from 6 sources: 2 prospective randomized studies; 1 prospective observational US diary study (DOSE); the US-based Hemostasis and Thrombosis Research Society (HTRS) Registry; the international ONE Registry; and the HemoRec registry (Czech data only). Data on prophylactic (PPX) rFVIIa use was obtained from 3 sources: 1 prospective randomized trial; 1 retrospective chart review study (PRO-PACT); and the HemoRec registry (Czech data). Data on intervals between high initial/subsequent doses and any further bypassing agent dose in OD treatment were analyzed from 3 sources that reported time of administration (DOSE, ONE and HemoRec). All studies had data safety monitoring in the form of explicit surveillance, positive affirmations of lack of adverse events, or chart reviews. Overlap in patient participation in studies could not be ruled out; however, all data are believed to be non-overlapping due to study timelines. Demographics, rFVIIa dosing, and frequency of TEs were analyzed and reported using descriptive statistics. Results: A total of 481 inhibitor patients reported using 61,734 rFVIIa doses either for OD treatment or PPX. Most patients had hemophilia A (87%) and were Caucasian (79%). Age ranged from 18y). All data sources included the use of rFVIIa doses higher than current US-recommendations. Overall, 52.2% of doses (45.9% in adults) were >120 mcg/kg, the highest dose referenced from previous clinical trials in the US package insert. For the152 patients from DOSE, ONE and HemoRec included in the dosing interval analyses, age ranged from 18y). Patients received 3,042 rFVIIa doses for 1,017 bleeds. These included 361 initial rFVIIa doses (36%) >240 mcg/kg, including 136 followed by a second dose of bypassing agent (130 with rFVIIa; 15 with pd-aPCC). There were 670 doses >240 mcg/kg used throughout treatments (22%), including 327 followed by a subsequent dose (311 with rFVIIa; 23 with pd-aPCC). Most subsequent doses (79%) occurred after >8 hrs. Conclusions: A review of 61,734 cumulative rFVIIa doses in studies with explicit safety monitoring demonstrates the use and safety of rFVIIa doses >90 mcg/kg in inhibitor patients. When doses >240 mcg/kg were followed by other bypassing agent doses, the dosing interval was >8 hrs after 79% of doses and >24 hrs after 53% of doses. Unlike MedWatch and passive surveillance where underreporting is common, we expect that the explicit surveillance in these studies would adequately identify TE events. Thus, the lack of TEs supports the overall low TE occurrence (0.28%) reported in the original registration trials in inhibitor patients using ≤90 mcg/kg. These data reinforce that the arterial thrombosis risk identified in meta-analyses outside of licensed indications (critical bleeds) are unique to those populations and do not apply to inhibitor patients. Furthermore, higher doses may provide an opportunity to improve bleed treatment with less frequent injections and decreased follow-up infusions. Disclosures: Shapiro: Novo Nordisk inc.: Consultancy, Research Funding, Speakers Bureau. Off Label Use: rFVIIa use in indicated population of congential hemophilia with inhibitors at doses that differ from those in the prescribing information. Neufeld:Novo Nordisk Inc.: Consultancy, Research Funding. Blanchette:Novo Nordisk: Consultancy. Chambost:Novo Nordisk: Consultancy. Salaj:Novo Nordisk: Consultancy. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Abstract 3374 Background: Acquired hemophilia (AH) is a rare disorder marked by the development of autoantibodies to factor VIII, with associated mortality of 8–22%. Patients present with bleeding episodes or unexpected bleeding at surgery, and a prolonged aPTT that does not correct with 1:1 mixing (2 hrs, 37°C). While the antibody often resolves with immunosuppression, most patients will need hemostatic treatment with bypassing agents including rFVIIa (NovoSeven RT) to resolve bleeding episodes or prevent bleeding during surgery. Methods: Data were analyzed from the HTRS registry (January 2004 – July 2011), supporting rFVIIa post-marketing surveillance, including data entered during the past 2 years on acute bleed and new surgical case report forms. Results: Of 154 identified AH patients, 99 had 217 reported bleeds and 35 underwent 56 surgical procedures. There were 125 (58%) rFVIIa-treated bleeds: 82 rFVIIa alone, 43 rFVIIa plus other agents/blood products, and 107 (86%) first-line rFVIIa therapy. For rFVIIa-treated bleeding episodes, 65 (52%) were in males and 60 (48%) in females; 85 were in white-non Hispanics and 24 (19%) in black non-Hispanics. Mean (median) age at bleeding was 66 (68) years. Median (range) of recent inhibitor titer was 16 (0–620) BU. Bleeds were spontaneous (85), traumatic (27), surgical/procedure-related (7), dental (2) or other (3). rFVIIa bleed treatment over a median 1 (range 1–60) day(s) are shown below: Efficacy of rFVIIa (physician-rated for each regimen), was reported as “bleeding stopped” in 105 (84%) episodes; “bleeding slowed” in 14 (11%) episodes (stopped with other agents in 3 episodes); “no improvement” in 5 (4%) episodes (no bleed stop date identified in 4, stopped with other agent in 1), and was not documented in 1. Excluding the 4 rFVIIa treatment failures where bleeding stopped after switching to another agent, overall rFVIIa efficacy was 97%. The only thromboembolic event was in a post-partum patient with transient neurologic symptoms. Of 56 surgical procedures ranging from minor procedures to major surgeries, 24 (43%) were rFVIIa-treated procedures (17 rFVIIa only). The 17 rFVIIa-treated patients had a mean (range) age of 72.4 (28–89) years, and were mostly in female and white non-Hispanic patients. Surgeries included central venous access (6), endoscopy (5), incision, drainage and grafting of hand hematomas (3), embolization of AVM (2), orthopedic procedures (2), cholecystectomy (1), colon biopsy (1), catheter removal (1), exchange of prostate treatment implant (1), venipuncture (1) and IVC placement (1). rFVIIa was used prior to surgery in 19 procedures and post-operatively in 15. rFVIIa treatment parameters are shown below: A single dose was used in 8/24 surgeries; maximum treatment was 19 days. Efficacy of any bypassing agents was rated as excellent/good or fair/partially effective in 20/24 (83%) procedures. Adequate hemostasis was achieved with planned regimens (all agents) in 16 procedures, with minor rFVIIa dose increases in 3, with additional agents in 2 (1 each PRBCs and Helixate), and “other” reported for 1. There were no thromboembolic events (TEs) reported. Conclusions: The HTRS registry now represents the 2nd largest data set reporting rFVIIa use in AH with 75% increase in rFVIIa-treated bleeds in the past 2 years, and is the only one to report data gathered on minor and major surgical procedures in AH. For acute bleeds and surgeries, median rFVIIa dosing was similar to doses recommended for routine treatment of bleeding episodes in patients with autoantibody inhibitors based on published studies. As AH surgeries are uncommon, we believe the surgeries reported relate to bleeding sites or venous access. No safety concerns were reported in this older population. As this registry was originally intended in part to track the safety of rFVIIa, these derived data may be somewhat biased and selective. Nevertheless, the data certainly indicate that rapid and safe hemostasis can be achieved for acute bleeding episodes and prevention of excessive bleeding during surgery with rFVIIa in an aging population where thrombogenicity is of concern. Disclosures: Ma: Novo Nordisk Inc.: Consultancy. Kessler:Novo Nordisk Inc.: Consultancy. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

Objective To identify factors associated with growth in children on growth hormone (GH) therapy using data from the American Norditropin Studies: Web-enabled Research (ANSWER) Program® registry. Methods GH-naïve children with GH deficiency, multiple pituitary hormone deficiency, idiopathic short stature, Turner syndrome, or a history of small for gestational age were eligible (N = 1,002). Using a longitudinal statistical approach, predictive factors were identified in patients with GHD for change from baseline in height standard deviation score (ΔHSDS) following 2 years of treatment. Results Gradual increases in ΔHSDS over time were observed for all diagnostic categories. Significant predictive factors of ΔHSDS, ranked by significance were: height velocity (HV) at 4 months > baseline age > baseline HSDS > baseline body mass index (BMI) SDS > baseline insulin-like growth factor I (IGF-I) SDS; gender was not significant. HV at 4 months and baseline BMI SDS were positively correlated, whereas baseline age, HSDS, and IGF-I SDS were negatively correlated with ΔHSDS. Conclusions These results may help guide GH therapy based on pretreatment characteristics and early growth response.