BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. ( BACKGROUNDCurrent hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.

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BACKGROUND Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients. METHODS In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies. RESULTS A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was −348 μg per liter (95% confidence interval, −517 to −179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo. CONCLUSIONS The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.)

Introduction: Nuwiq â (human-cl rhFVIII) is a 4 th generation recombinant human FVIII, without chemical modification or protein fusion, produced in a human cell-line. Aims/Methods: This study (NuPreviq) was a prospective, open-label, multicentre, phase IIIb study of the efficacy and safety of personalized prophylaxis with Nuwiq â in 66 previously treated adults with severe haemophilia A. NuPreviq had three phases: (i) a 72-h pharmacokinetic (PK) phase; (ii) a 1-3 month standard prophylaxis phase; and (iii) a 6-month personalized prophylaxis phase. The personalized prophylaxis regimen was based on individual PK modelling for each patient according to whether their PK profile most closely fitted a two-or one-compartment model (NuPreviq approach). In cases of uncertainty, a noncompartment model was applied. Results: The median dosing interval during personalized prophylaxis was 3.5 days, with 57% of patients on ≤2 weekly dosing. Mean annualized bleeding rates during personalized prophylaxis were 1. .1% of patients were spontaneous bleed-free. Compared with standard prophylaxis, median weekly prophylaxis dose was reduced by 7.2% from 100.0 to 92.8 IU kg À1 during the last 2 months of personalized prophylaxis. There were no FVIII inhibitors or treatment-related serious or severe adverse events. Conclusion: PK-guided personalized prophylaxis with Nuwiq â provided bleeding protection and enabled the dosing interval to be extended to twice weekly or less in many patients and an overall dose reduction.

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In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough FVIII levels. Thus, personalized prophylaxis should take into account variables other than FVIII:C. Large prospective trials are needed to verify ETP as a marker for spontaneous bleeding.

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Background: Interferon alfa (IFNa) based therapies have been successfully applied in myeloproliferative neoplasms (MPN) for over thirty years. Several uncontrolled phase II trials have independently shown high rates of hematologic, splenic and sustained mutant JAK2 molecular responses in Polycythemia vera (PV) patients. However, a head-to-head assessment versus other treatment options in confirmatory trials has been lacking so far. Here we report 12 month data from a randomized controlled phase III trial comparing the novel, long-acting Ropeginterferon alfa-2b (AOP2014) with hydroxyurea (HU) in PV patients. Study design: Randomized, controlled, parallel group multicenter phase III trial assessing efficacy, safety and tolerability in patients diagnosed with PV according to WHO2008 criteria, either naïve to cytoreduction or HU experienced (but neither intolerant nor complete responders, cumulative HU exposure max. 3 years). The primary endpoint was non-inferiority of AOP2014 vs. HU at 12 months of therapy in terms of complete hematological response (CHR) rate. CHR was defined as normal hematocrit, leukocyte and platelet counts, spleen size and absence of phlebotomy in the preceding 3 months. As important secondary endpoint the effect of treatment on mutant JAK2 allele burden was assessed as rate of complete and partial molecular response (C/PMR) rate according to modified ELN criteria. Both cohorts are followed up further maintaining the original randomization for assessing effects of prolonged therapy. Results: 257 patients were randomized in 48 sites in 13 European countries and treated with response-driven escalating doses of either AOP2014, or HU. 62% of patients were naïve to cytoreduction, 38% HU experienced; 19% had a previous thrombotic event. Response-driven dose escalation was done in both treatment arms applying up to 10 dose levels (50-500µg AOP2014 every other week, or 250-3000 mg HU daily). Both treatments were well tolerated. The drop-out rate after 12 months was low with ~15% in both arms, the majority of drop-outs were due to administrative reasons (bi-weekly hospital visits). This presentation will provide the detailed analysis of primary and secondary endpoints of the trial, which is still blinded as of 4th Aug 2016. Preliminary pooled analysis revealed that at 12 months 45% of patients had a hematologic response: mean Hct values dropped from 48% to 42%, leukocyte counts from 12 to 6 *109/L and platelets from 530 to 260 *109/L. Need for phlebotomy within 3 months dropped from 86% to 6%. 37% of patients achieved a JAK2 molecular response (PMR or CMR), mean mutant JAK2 allele burden went from 42,5% to 28,7%. Conclusions: This is the first phase III trial formally assessing efficacy, safety and tolerability of Ropeginterferon alfa-2b versus HU. Both cohorts are followed-up for prolonged treatment duration, and it is expected that the currently available and emerging data will establish the role of Ropeginterferon alfa-2b as first-line treatment for PV. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG, Novartis, Celgene, Baxalta: Consultancy, Honoraria, Research Funding. Klade:AOP Orphan: Employment. Georgiev:Alnylam Pharmaceuticals: Consultancy. Illes:University of Debrecen faculty of medicine department of hematology: Employment. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding.