ALBERT

Description: Introduction Hemophilia A and hemophilia B are rare bleeding disorders characterized by insufficient thrombin generation due to deficiencies in factors VIII or IX, respectively. Standard treatment for hemophilia is currently based on replacement of the deficient factor with factor concentrate. This, unfortunately, subjects the patient to the risk of developing neutralizing antibodies, or inhibitors, against replacement factor VIII or IX. Individuals with inhibitors become refractory to standard replacement therapy, a serious complication for as many as one-third of patients with severe hemophilia A and a lower proportion of patients with hemophilia B. Fitusiran is a once-monthly subcutaneously administered investigational RNA interference therapeutic that targets antithrombin (AT) to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or hemophilia B with or without inhibitors. In September 2017, fitusiran dosing in the Phase 2 open-label extension (OLE) study was temporarily suspended to investigate a case of fatal cerebral venous sinus thrombosis. Following this investigation, fitusiran dosing resumed in December 2017 with protocol amendments for bleed management dosing and safety monitoring. During the temporary dosing suspension, AT levels, TG, bleeding events, and frequency of factor replacement and bypassing agents were assessed. Methods Before the dosing suspension, 33 patients (hemophilia A=27, hemophilia B=6) were enrolled, of whom 28 patients continued treatment over 20 months in the Phase 2 OLE study, with a median of 11 months on study. As of June 2018, data collected monthly during the clinical hold included AT levels, TG, and description and management of treated bleeding events before and during the clinical hold, which were used to estimate annualized bleeding rates (ABRs) and bleeding rates per month. Results AT activity in patients previously receiving fitusiran demonstrated a progressive increase during the interruption of fitusiran dosing. Median %AT increased to 〉60% after a 5-month period compared with the last data point before dosing interruption. These data confirm our previous findings that discontinuation of fitusiran results in gradual recovery of AT activity over time. Subjects also demonstrated a concomitant steady decrease in TG during the interruption of fitusiran dosing, which occurred over a similar time course to that of AT recovery. Consistent with both the increase in AT activity and decrease in TG, preliminary analysis shows the median overall ABR increased from 1.43 events/year before the dosing interruption to 6.07 events/year during the dosing interruption. Conclusions During a period of fitusiran dosing suspension, recovery of AT activity was accompanied by a decrease in TG and an increase in bleeding events. These observations provide support for the therapeutic hypothesis that AT activity lowering by fitusiran leads to an increase in TG and improved hemostasis. Phase 3 studies of fitusiran are ongoing. Disclosures Ragni: Bioverativ: Consultancy, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding. Georgiev:Alnylam: Consultancy. Lissitchkov:Novo Nordisk: Other: Investigator fees as a participant of the clinical trial. Austin:Pfizer: Research Funding. Chowdary:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Freeline: Consultancy; Bayer: Honoraria; Baxalta (Shire): Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum AB (Sobi): Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foster:Sanofi Genzyme: Employment. Yu:Sanofi Genzyme: Employment. Benson:Sanofi Genzyme: Employment. Madigan:Alnylam Pharmaceuticals Inc: Employment. Nguyen:Alnylam Pharmaceuticals Inc: Employment. Ali:Sanofi Genzyme: Employment. Kadam:Sanofi Genzyme: Employment. Jain:Sanofi Genzyme: Employment. Pasi:Octapharma: Honoraria; Catalyst Bio: Honoraria; Bayer: Speakers Bureau; Shire: Speakers Bureau; NovoNordisk: Speakers Bureau; Sobi: Honoraria; Apcintex: Honoraria; Biomarin: Honoraria, Research Funding; Pfizer: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding.

Description: Introduction: β-thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect characterized by ineffective erythropoiesis and impaired RBC maturation. Luspatercept is a first-in-class erythroid maturation agent under development to treat patients with β-thalassemia. Luspatercept binds to select TGFβ superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis (Suragani RN, et al. Nat Med. 2014;20:408-14). We report the results of a phase 3, randomized, double-blind, placebo-controlled study to determine the efficacy and safety of luspatercept in adult β-thalassemia patients requiring regular RBC transfusions. ClinicalTrials.gov identifier: NCT02604433. Methods: Eligible patients were aged ≥ 18 years; had β-thalassemia or hemoglobin (Hb) E/β-thalassemia (compound β-thalassemia mutation and/or multiplication of α-globin genes was allowed); and required regular transfusions of 6-20 RBC units in the 24 weeks prior to randomization with no transfusion-free period ≥ 35 days during that time. Patients were randomized 2:1 to receive either luspatercept, at a starting dose level of 1.0 mg/kg with titration up to 1.25 mg/kg, or placebo, subcutaneously every 3 weeks for ≥ 48 weeks. Patients in both treatment arms continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hb level. The primary endpoint was a ≥ 33% reduction in transfusion burden (with a reduction of ≥ 2 RBC units) during weeks 13-24, when compared with a 12-week baseline period. Key secondary endpoints included: ≥ 33% reduction in RBC transfusion burden at weeks 37-48, ≥ 50% reduction in transfusion burden at weeks 13-24, ≥ 50% reduction in transfusion burden at weeks 37-48, and mean change in transfusion burden at weeks 13-24. Achievement of ≥ 33% reduction in RBC transfusion burden over any consecutive 12 weeks on study was also evaluated. Results: † A total of 336 patients were randomized, of whom 332 were treated. Median age was 30 years (range 18-66) and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment. 58% of patients in each arm had undergone splenectomy. B0/B0 genotype (classification according to the HbVar database) was observed in 68 of 224 (30.4%) and 35 of 112 (31.3%) patients in the luspatercept and placebo arms, respectively. 48 of 224 (21.4%) patients in the luspatercept arm achieved the primary endpoint versus 5 of 112 (4.5%) patients receiving placebo (odds ratio 5.79, P 〈 0.0001). 44 of 224 (19.6%) patients receiving luspatercept achieved a ≥ 33% reduction in RBC transfusion burden at weeks 37-48 compared with 4 of 112 (3.6%) patients receiving placebo (P 〈 0.0001). Of 224 patients receiving luspatercept, 17 (7.6%) and 23 (10.3%) achieved a ≥ 50% reduction in RBC transfusion burden at weeks 13-24 and 37-48, respectively, compared with 2 (1.8%) and 1 of 112 (0.9%) patients receiving placebo (P = 0.0303 and P = 0.0017, respectively). The difference of mean change from baseline in transfusion burden from week 13 to week 24 was 1.35 units (P 〈 0.0001). 158 of 224 (70.5%) patients receiving luspatercept achieved a ≥ 33% RBC transfusion reduction over any consecutive 12 weeks compared with 33 of 112 (29.5%) patients receiving placebo (P 〈 0.0001); statistically significant differences were also noted for all other transfusion burden reduction endpoints. Adverse events (AEs) observed in the study were generally consistent with previously reported phase 2 data. Treatment-emergent AEs leading to dose delay or dose reduction were similar between treatment arms. No patient deaths were reported for those treated with luspatercept. Conclusions: Treatment with luspatercept resulted in significant reductions in RBC transfusion burden in adults with transfusion-dependent β-thalassemia. Luspatercept was generally well tolerated in this patient population. † As of May 11, 2018, cutoff date. Disclosures Cappellini: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sanofi/Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Vifor: Membership on an entity's Board of Directors or advisory committees. Viprakasit:F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Taher:Protagonist Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Ionis Pharmaceuticals: Consultancy; La Jolla Pharmaceutical: Research Funding; Celgene Corp.: Research Funding. Georgiev:Alnylam: Consultancy. Coates:Celgene Corp.: Consultancy; ApoPharma: Consultancy, Honoraria; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria. Voskaridou:Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding. Forni:Novartis: Research Funding; Roche: Research Funding; Celgene: Research Funding. Perrotta:Acceleron Pharma: Research Funding; Novartis: Research Funding. Lal:Celgene Corporation: Research Funding; Bluebird Bio: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Insight Magnetics: Research Funding; Novartis: Research Funding; Terumo Corporation: Research Funding. Kattamis:ApoPharma: Honoraria; Vifor Pharma: Consultancy; CELGENE: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Vlachaki:Novartis: Honoraria. Origa:Cerus Corporation: Research Funding; Bluebird Bio: Consultancy; Novartis: Honoraria; Apopharma: Honoraria. Aydinok:TERUMO: Research Funding; Protagonist: Other: SSC; CRISPR Tech: Other: DMC; Cerus: Honoraria, Research Funding; La Jolla Pharmaceuticals: Research Funding; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding. Ho:Takeda: Honoraria, Other: travel to meeting; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Celgene: Other: Travel to meeting. Chew:Celgene: Research Funding. Tantiworawit:Celgene: Honoraria, Research Funding, Speakers Bureau. Shah:Novartis: Honoraria, Speakers Bureau; Sobi/Apotex: Honoraria; Celgene Corp: Other: Steering committee; Roche: Other: Advisory board meeting. Neufeld:Celgene Corp.: Consultancy, Other: Steering committee; Acceleron Pharma: Consultancy. Laadem:Celgene: Employment, Equity Ownership. Shetty:Celgene: Employment, Equity Ownership. Zou:Celgene Corporation: Employment, Equity Ownership. Miteva:Celgene Corporation: Employment, Other: grants. Zinger:Celgene Corporation: Employment. Linde:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership; Fibrogen: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Hermine:AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene Corporation: Research Funding; Hybrigenics: Research Funding; Erythec: Research Funding; Novartis: Research Funding. Porter:Cerus: Honoraria; Agios: Honoraria; Novartis: Consultancy. Piga:La Jolla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Honoraria; Apopharma: Honoraria, Research Funding; Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Acceleron: Research Funding.

Description: Background: Interferon-alpha (IFN) is being used in myeloproliferative neoplasms (MPNs) since years and remains the only known treatment with disease-modifying potential. Ropeginterferon alfa-2b (Ropeg) is a novel mono-pegylated IFN, with reduced dosing frequency and improved tolerability. Here, we report 3 years clinical data from the phase III PROUD/CONTI-PV trials with an additional emphasis on the first comprehensive, prospective, randomized, controlled genomic profiling including not only JAK2V617F, but longitudinal targeted sequencing to identify non-JAK somatic mutations and chromosomal aberrations. Study design: 254 PV patients (WHO 2008 criteria, naïve to cytoreduction or HU pretreated but not resistant) were randomized to receive Ropeg or hydroxyurea (HU) in the PROUD-PV study and were rolled over to CONTI-PV study after 12 months, with the option to switch from HU to best-available-therapy (BAT). Efficacy assessment included complete hematological response (CHR, by ELN criteria), and CHR plus symptom improvement (PV-related symptoms and signs including clinically significant splenomegaly). Secondary endpoints included JAK2V617F molecular response (MR, modified ELN criteria). Next-generation-sequencing (NGS, TruSight Myeloid Panel, Illumina) and genome-wide analysis (SNP 6.0, Affymetrix) was applied comprehensively as exploratory genetic work-up. Results: 83 (Ropeg) and 70 (HU/BAT) patients completed the 36-month efficacy analysis time point, mean treatment duration for safety analysis was 3.8 years. Median doses in the third year remained constant: 425 µg Ropeg every 2 weeks and 1,000 mg HU per day. In the HU/BAT arm over 97% of patients remained treated with HU. After 36 months of treatment, maintenance of higher responder rates (full analysis set) was shown in the Ropeg arm compared to HU/BAT for CHR (70.5% vs. 51.4%; p=0.0122; RR [95% CI]: 1.38 [1.07-1.79]) and for CHR plus symptom improvement (52.6% vs. 37.8%; p=0.0437; RR [95% CI]: 1.42 [1.01-2.00]). In contrast to HU/BAT, response rates were steadily increasing in the Ropeg arm throughout 24 months of treatment and remained constant after 36 months. Regarding safety, comparable numbers of patients experienced adverse events (89.8% for Ropeg, 90.6% for HU) and treatment-related adverse events (74.8% for Ropeg, 78.7% for HU). The most common (〉10%) treatment-related adverse events anemia, thrombocytopenia and leukopenia occurred more frequently under HU, whereas GGT increase was mainly observed under Ropeg. No new safety signals appeared in the third year of treatment. Regarding JAK2V617F, after 36 months 66.0% of patients in the Ropeg arm but only 27.0% in the HU/BAT arm had achieved MR (p

Description: Background: Hemophilia is a bleeding disorder characterized by a profound defect in the ability to generate sufficient thrombin for effective hemostasis. Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting the endogenous anticoagulant antithrombin (AT) as a means to improve thrombin generation and promote hemostasis in patients with hemophilia. Preliminary data from an ongoing Phase 1, four part (Part A: healthy volunteers; Parts B and C: patients with moderate to severe hemophilia A or B; Part D: patients with hemophilia A or B with inhibitors), multi-center, study showed that fitusiran was generally well tolerated and that administration of once-monthly SC doses of fitusiran led to dose-dependent AT lowering, thrombin generation increase, and decrease in bleeding frequency (Pasi KJ, et al. Haemophilia 2016, 22[Suppl 4]). The purpose of this abstract is to report the updated safety, pharmacodynamics (PD), and clinical activity of fitusiran in patients with hemophilia without inhibitors from the Phase 1 (Part C) as well as long term data from the Phase 1/2 extension study. Methods: We are conducting a multi-center Phase 1 study (NCT02035605) followed by a multi-center Phase 1/2 extension study (NCT02554773) in hemophilia A and B patients. Patients received SC administered, weekly (Part B) or once-monthly (Part C) weight-based or fixed doses of fitusiran. Primary endpoints include safety and tolerability; secondary endpoints include AT activity, thrombin generation and exploratory evaluation of bleed pattern. After receiving 3 monthly doses in the Phase 1 study, all patients were eligible to continue monthly dosing in the Phase 1/2 extension study. Standard replacement factor VIII or IX was utilized to manage any breakthrough bleeds. Results: Previously reported safety data demonstrated that fitusiran was generally well tolerated in hemophilia A or B patients without inhibitors (Phase 1, Parts B and C) and that there were no serious adverse events related to study drug and no thromboembolic events. In Phase 1, Part C, patients initially received weight-based doses ranging from 225 to 1800mcg/kg or a fixed dose of 80mg. Fitusiran dosing resulted in dose-dependent lowering of AT with a mean maximal AT lowering of 87 ± 1% at the 80mg fixed dose and mean thrombin generation increase of 289% relative to baseline with AT lowering 〉75%. Exploratory analysis of bleed events (Phase 1, Part C) showed a median annualized bleeding rate (ABR) of zero during the defined observation period. As of July 2016, a total of 25 non-inhibitor patients have been enrolled in the entire Phase 1 study and 16 of these patients have entered the ongoing Phase 1/2 extension study. All patients who enrolled in the Phase 1/2 extension study transitioned to a fixed monthly fitusiran dose of 50mg or 80mg. Updated safety, tolerability and clinical activity among all non-inhibitor patients will be presented. Conclusions: Emerging clinical data suggest that targeting AT is generally safe and could be a promising approach for promoting hemostasis in hemophilia. The potential for low volume SC administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make fitusiran a potentially encouraging investigational therapy. Disclosures Ragni: Tacere Benitec: Consultancy; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; OPKO: Research Funding; Vascular Medicine Institute: Research Funding; SPARK: Research Funding. Georgiev:Alnylam Pharmaceuticals: Consultancy. Chowdary:Sobi: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria. Rangarajan:Novo Nordisk: Research Funding; Baxter: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Biogen: Consultancy; Biotest: Research Funding; Pfizer: Research Funding; Grifols: Consultancy, Research Funding. Soh:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Sorenson:Alnylam Pharmaceuticals: Employment, Equity Ownership. Pasi:Pfizer: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy, Honoraria; Biogen: Consultancy, Honoraria.

Description: Background: Hemophilia A and B are bleeding disorders characterized by a profound defect in thrombin generation (TG). Furthermore, in the presence of normal levels of endogenous anticoagulants a deficiency in factor VIII and IX results in major hemostatic imbalance and a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin (AT) that aims to restore the hemostatic balance by increasing TG. Methods: We are conducting a phase 1 multi-center study (NCT02035605) in healthy volunteers and patients with moderate to severe hemophilia A or B. Part A of this study has been completed and assessed a single ascending dose study in healthy volunteers. Parts B and C are multiple ascending dose studies in patients with hemophilia who are receiving weekly or monthly dosing, respectively. Primary endpoints are safety and tolerability. Secondary endpoints include PK, AT knockdown; change in thrombin generation and whole blood clot formation as measured by Calibrated Automated Thrombin generation and ROTEM thromboelastometry. Exploratory endpoints include evaluations of bleed pattern and control. Results: Part A enrolled 4 healthy volunteers, randomized (3:1) to 30 mcg/kg ALN-AT3 or placebo; no serious adverse events (SAE) or injection site reactions were observed. A total of 12 patients with severe hemophilia (10 hemohilia A; 2 hemophilia B) were enrolled in Part B and received 3 weekly subcutaneous doses of ALN-AT3 at 15 (n=3), 45 (n=6), and 75 (n=3) mcg/kg. Similar to part A, weekly administration of ALT-AT3 was generally safe and well tolerated in patients with hemophilia; no SAEs, discontinuations, clinical thromboembolic events or clinically significant D-dimer increases were reported. In the 75 mcg/kg dosing cohort, the mean maximum AT knockdown was 59% (p

Description: 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.

Description: Background: Development of inhibitory antibodies, also known as "inhibitors," to replacement factor is considered the most serious unmet need in hemophilia and occurs in up to 30% of persons with severe hemophilia A, and 3-5% of persons with severe hemophilia B. Once inhibitors are present in high titer, treatment or prevention of bleeding can become more difficult due to the decreased responsiveness to factor concentrates, requiring bypassing agents (BPA) for bleed management. Current BPAs have a short half-life and are sub-optimally effective. Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting the endogenous anticoagulant antithrombin (AT) as a means to improve thrombin generation and promote hemostasis in patients with hemophilia. Preliminary data from an ongoing Phase 1, multi-center, study showed that fitusiran was generally well tolerated in patients with hemophilia A or B with and without inhibitors and that administration of once-monthly SC doses of fitusiran led to dose-dependent AT lowering, thrombin generation increase, and decrease in bleeding frequency (Pasi KJ, et al. Haemophilia 2016, 22[Suppl 4]). Here we report the updated safety, pharmacodynamic (PD) effect, and clinical activity of fitusiran in patients with hemophilia with inhibitors as well as long term data from the Phase 1/2 extension study. Methods: We are conducting a multi-center Phase 1, four part (Part A: healthy volunteers; Parts B and C: patients with moderate to severe hemophilia A or B; Part D: patients with hemophilia A or B with inhibitors) study (NCT02035605) followed by a multi-center Phase 1/2 extension study (NCT02554773). Primary endpoints include safety and tolerability; secondary endpoints include AT activity, thrombin generation and exploratory evaluation of bleed pattern. In Part D, patients with inhibitors received once-monthly SC fixed doses of 50 or 80mg fitusiran. After receiving 3 monthly doses in the Phase 1 study, all patients were eligible to continue monthly dosing in the Phase 1/2 extension study. Utilization of BPA for breakthrough bleed management was permissible in these patients. Results: Part D of the Phase 1 study included 12 hemophilia A or B patients with inhibitors in 2 dosing cohorts (50mg SC, qM dosing cohort, n=6; 80mg SC, qM dosing cohort, n=6). Within the 50mg dosing cohort there were five patients with severe hemophilia A with inhibitors and one patient with severe hemophilia B with inhibitors; mean age: 33 ± 7 years; mean weight: 73 ± 17kg. Previously reported safety data from the 50mg dosing cohort demonstrated fitusiran was generally well tolerated in hemophilia A or B patients with inhibitors and that there were no serious adverse events related to study drug and no thromboembolic events. Monthly administration of fitusiran at the 50mg dose led to a mean maximal AT lowering of 81 ± 2% and mean maximal thrombin generation increase of 368 ± 113%. A preliminary, post-hoc analysis suggested a 49-100% reduction in bleeding frequency at the lower dose of 50mg during initial follow-up in the Phase 1 study. As of July 2016, the 80mg dose cohort has been fully enrolled and includes 6 patients with hemophilia A with inhibitors; mean age: 39 ± 15 years; mean weight: 75 ± 19kg, and 5 of the 6 patients in the initial 50mg cohort have transitioned to the Phase 1/2 extension study. Follow-up in the Phase 1, 80mg cohort and Phase 1/2 extension study is ongoing. Updated safety, tolerability and clinical activity from the Phase 1 and Phase 1/2 extension studies among all 12 patients with inhibitors will be presented. Conclusions: Emerging clinical data suggest that targeting AT is generally safe and could be a promising approach for promoting hemostasis in patients with hemophilia with inhibitors. Furthermore, the potential for low volume SC administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make fitusiran a potentially encouraging investigational therapy. Disclosures Pasi: Biogen: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Georgiev:Alnylam Pharmaceuticals: Consultancy. Chowdary:Bayer: Honoraria; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ragni:Novo Nordisk: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Genentech: Research Funding; SPARK: Research Funding; Baxalta: Research Funding; CSL Behring: Research Funding; Shire: Consultancy; Vascular Medicine Institute: Research Funding; Tacere Benitec: Consultancy; OPKO: Research Funding. Soh:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Sorenson:Alnylam Pharmaceuticals: Employment, Equity Ownership.

Description: Introduction: The key treatment goals for polycythemia vera (PV) are to prevent thromboembolic events and minimize the risk of progression, ultimately modifying the natural history of the disease by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV study, long-term treatment with ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as hematological and molecular parameters over a four-year period. Methods: Cytoreduction-naïve or HU-pre-treated patients aged ≥18 years diagnosed with PV according to WHO 2008 criteria were eligible. A total of 257 patients were randomly allocated to ropeg or hydroxyurea at individualized doses for 12 months in the initial study phase (PROUD-PV). In the ongoing extension phase (CONTINUATION-PV), patients in the hydroxyurea arm were permitted to switch to best available treatment. Efficacy assessments included a longitudinal analysis of complete hematological response (CHR) and complete molecular response (CMR; JAK2V617F was determined using real-time PCR [ipsogen® JAK2 MutaQuant® kit; QIAGEN GmbH]), defined by modified ELN criteria. Discontinued patients were considered non-responders. A data snapshot was performed once all patients reached 48 months of treatment; all available safety data were included. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension phase. At the time of analysis 139 patients remained on study: 74/95 in the ropeg arm and 65/76 in the control arm. Almost all patients in the control arm (〉97% at the last available assessment) continued on HU. The rate of patients in CHR was significantly higher in the ropeg arm than in the control arm in the 4th year (60.6% versus 43.4%; p=0.02), as seen after 2 and 3 years of treatment. In line with this effective control of hematologic parameters by ropeg, a very low rate of major thromboembolic adverse events was observed in the ropeg arm: 0.0%, 0.0% and 1.1% of patients in the 2nd, 3rd and 4th years, respectively. In the control arm, rates of major thromboembolic adverse events in the 2nd, 3rd and 4th year were 0.9%, 1.4% and 0.0%, respectively. The median JAK2V617F allele burden declined from 37.3% at baseline to 9.8% over 4 years in the ropeg arm, whereas in the control group, the median allele burden increased from 38.1% to 43.1% in the same period (p

Description: Introduction: Patients with polycythemia vera (PV) require life-long treatment to prevent thromboembolic events and minimize the risk of progression. Ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) may ultimately modify the natural history of PV by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV studies, long-term treatment with ropeg was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as evolution of hematologic and molecular parameters over five years. Methods: Patients aged ≥18 years and diagnosed with PV according to WHO 2008 criteria who were either cytoreduction-naïve or hydroxyurea (HU)-pre-treated for 〈 3 years were enrolled. A total of 257 patients were randomized 1:1 (stratified by age 〉 60 years, prior thromboembolic events, and HU pre-treatment) to receive ropeg or HU at individualized doses for 12 months in the initial study (PROUD-PV). In the extension study (CONTINUATION-PV), patients in the HU arm were permitted to switch to best available treatment. Efficacy assessments included hematologic parameters, phlebotomy need, JAK2V617F allele burden, and molecular response defined by modified ELN criteria. An interim analysis was conducted once all patients reached 5 years of treatment; efficacy data for patients enrolled in the extension study and all available safety data were analyzed. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension study. Most patients in the control arm continued to receive HU (88% at month 60). At the time of this 5-year analysis, 70 patients in the ropeg arm and 57 in the control arm remained on study; discontinuation rates were balanced between the treatment arms (ropeg: 26.3%; control: 25.0%). Hematocrit