Abstract: BAY 81‐8973 (Kovaltry ® ), a full‐length, unmodified, recombinant human factor VIII, provided excellent bleeding control for patients with haemophilia A in the pivotal 1‐year LEOPOLD I trial. The LEOPOLD I extension evaluated long‐term efficacy and safety of BAY 81‐8973 prophylaxis. Methods After completing LEOPOLD I, patients continued receiving 20‒50 IU/kg BAY 81‐8973 two‐ or three‐times weekly in the extension. Outcomes included annualised bleeding rate (ABR) and haemostasis during surgery. Results Fifty‐five patients aged 12‐65 years participated in the extension. Median (range) exposure days during the 2‐year total study period was 309 (115‐355). No patient switched regimens. Median (Q1; Q3) ABR for all bleeds was 2.0 (1.0; 6.1) during the pivotal study, 2.0 (0.0; 5.2) during the extension, and 2.0 (0.5; 5.5) combined. The proportion of joint bleeds affecting target joints decreased (pivotal study: 90.9%, extension: 60.0%). Haemostasis was assessed as excellent/good in all five major surgeries. One serious adverse event (myocardial infarction) occurred in a patient with cardiovascular risk factors. No patients developed inhibitors. Conclusions BAY 81‐8973 prophylaxis efficacy outcomes in the pivotal study were maintained or, in the case of joint protection, improved during the extension, with a safety and tolerability profile consistent with previous experience.

Abstract: Introduction Emicizumab - a bispecific humanized monoclonal antibody given subcutaneously - bridges FIXa and FX to restore the function of missing FVIIIa. It is approved for routine prophylaxis in people with hemophilia A (PwHA) with inhibitors of all ages. Previous data from the HAVEN 2 study of emicizumab in pediatric PwHA with inhibitors 〈 12 years (data cut-off May 8, 2017) showed once-weekly (QW) dosing provided effective bleed control and was well tolerated (Young et al. Blood 2017). We present the primary analysis of the study, including analyses of the bi-weekly (Q2W) and monthly (Q4W) dosing regimens. Methods HAVEN 2 (NCT02795767) enrolled PwHA with inhibitors aged 〈 12 years (or 12-17 years if 〈 40kg) previously treated with episodic or prophylactic bypassing agents (BPAs) to receive emicizumab prophylaxis for ≥52 weeks. A loading dose of 3mg/kg emicizumab was given QW for 4 weeks followed by a maintenance dose of 1.5mg/kg QW, 3mg/kg Q2W or 6mg/kg Q4W (cumulative dose identical for all regimens). Efficacy analyses included annualized bleed rates (ABRs) for all bleed endpoints and an intra-individual comparison with ABR on prior BPAs from a prospective non-interventional study (NIS; NCT02476942). Safety assessments included records of adverse events (AEs), serious AEs (SAEs), AEs of interest and immunogenicity. Pharmacokinetics (PK) across dosing regimens was also analyzed. Results Eighty-eight patients were enrolled (n=68 QW; n=10 Q2W; n=10 Q4W), 18 of whom were aged ≤2 years old. At clinical cut-off (April 30, 2018), the median (range) emicizumab exposure for each cohort was 57.2 (17.1-92.1), 20.1 (18.1-24.1), and 18.1 (8.1-24.1) weeks, respectively; 59 patients in the QW cohort completed 52 weeks on study; 3 patients discontinued due to switching to commercial emicizumab (n=2 QW) or lack of efficacy (n=1 Q4W). In the QW, Q2W, and Q4W cohorts, the ABR in treated patients aged 〈 12 years was 0.3 (95% confidence interval [CI]: 0.17-0.50), 0.2 (0.03-1.72), and 2.2 (0.69-6.81) for treated bleeds, respectively. Zero treated bleeds were reported in 50/65 (76.9%), 9/10 (90.0%), and 6/10 (60.0%) patients, respectively. Across cohorts, all patients experienced ≤3 treated bleeds (Table 1). Overall, 30 treated bleeds were reported (n=22 QW; n=1 Q2W; n=7 Q4W): 19 occurring in a joint (n=12 QW; n=1 Q2W; n=6 Q4W), 4 in a muscle (n=3 QW; n=1 Q4W), and 7 classified as 'other' (n=7 QW). The majority (25/30; 83.3%) of treated bleeds were traumatic and 5/30 (16.7%) were spontaneous. An intra-individual comparison of 18 patients 〈 12 years old in the QW cohort who had participated in the NIS (15 and 3 on prior prophylactic and episodic BPAs, respectively) showed a 99% (95% CI: 97.7-99.4) reduced risk of treated bleeds with emicizumab compared with prior BPAs (Figure 1). Emicizumab was safe and well tolerated. No thromboembolic or thrombotic microangiopathy events or deaths occurred. The most common AEs are listed in Table 2. Seventeen patients experienced 21 SAEs. Four patients tested positive for anti-drug antibodies (ADA), two of whom had ADA with neutralizing potential based on reduced emicizumab levels; one discontinued emicizumab treatment and the other had no bleeds as of the clinical cut-off date. Mean steady-state trough concentrations of emicizumab were maintained at therapeutic levels across all regimens (Figure 2). Trough plasma concentrations increased with loading doses until Week 5, then were maintained at approximately 50, 45-50 and 38μg/mL with QW, Q2W and Q4W dosing, respectively. As of the data cut-off, 21 minor surgical procedures had been carried out, 14 (66.7%) of which were central venous access device (CVAD) removals. Conclusions To our knowledge, HAVEN 2 is the largest prospective study in pediatric PwHA with inhibitors to date, and demonstrates that emicizumab prophylaxis is well tolerated and can prevent or substantially reduce bleeds in this population. Meaningful efficacy and PK were maintained with less frequent dosing, with no new safety signals, suggesting the potential for reduced treatment burden in the pediatric population. Additionally, the large number of CVAD removals suggests that prophylactic emicizumab may offer a new and effective standard of care for hemophilia that is also more convenient and less invasive, and may offer the potential for flexible treatment regimens based on patient needs. Disclosures Young: Genentech/Roche: Consultancy, Honoraria, Research Funding; Novo Nordisk: Honoraria; Shire: Honoraria. Liesner:Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Roche: Research Funding; Sobi: Speakers Bureau. Sidonio:Uniqure: Honoraria; CSL Behring: Honoraria; Shire: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; Kedrion/Grifols: Research Funding; Bioverativ: Honoraria, Research Funding; Biomarin: Honoraria; Novo Nordisk: Honoraria. Oldenburg:Chugai: 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: 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; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jimenez-Yuste:NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; CSL Behring: Consultancy; Octapharma: Consultancy, Research Funding; Grifols: Consultancy, Research Funding. Mahlangu:Alnylam: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Biomarin: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Kruse-Jarres:Grifols: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Terumo BCT: Other: CPC Clinical Research; Novo Nordisk: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; Bayer: Consultancy; CSL Behring: Consultancy. Chang:Genentech: Employment, Equity Ownership. Uguen:F.Hoffmann-LaRoche: Employment. Doral:Genentech: Employment. Schmitt:F. Hoffmann-La Roche: Employment, Equity Ownership. Levy:Genentech/Roche: Employment, Equity Ownership. Shima:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Mancuso:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biotest: 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; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion: Consultancy; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: In hemophilia patients with inhibitors, hemostasis can be achieved using bypass agents: activated plasma-derived prothrombin complex concentrates (aPCC), recombinant Factor VIIa (FVIIa), or emicizumab - that can only manage hemophilia A. Marzeptacog alfa (activated) (MarzAA), an engineered recombinant FVIIa with enhanced biological properties enabling subcutaneous (SQ) delivery was developed using a rational protein design approach. It has 7-fold increased catalytic activity and prolonged duration of effect demonstrated in a single-dose intravenous (IV) study that documented safety. Daily SQ dosing in dogs demonstrated achievement of stable trough levels of MarzAA that are believed to be effective for prophylaxis. Aims: Phase 2/3 Study MAA-201 (NTC03407651) will determine if SQ MarzAA can provide effective prophylaxis. This study complies with the Declaration of Helsinki and is approved by recognized research ethics committees. Up to 12 subjects with inhibitors, who have an annualized bleeding rate ≥12 (ABR), and sign informed consent, will participate. Methods: After an 18 mg/kg MarzAA IV bolus, pharmacokinetics and coagulation parameters were measured for 24 hours followed by 30 mg/kg MarzAA SQ with pharmacokinetics and coagulation parameters measured for a further 48 hours to calculate bioavailability. Subjects then received daily 30 mg/kg MarzAA SQ for 50 days. If no spontaneous bleeding events occurred the subject proceeded to safety follow-up 3 weeks after the last dose. If spontaneous bleeding occurred, dose escalation occurred sequentially to 60, 90 or 120 mg/kg for 50 daily doses as needed (fig 1). Subjects were monitored for treatment-related changes in Quality of Life measures and tested for anti-drug antibodies to MarzAA and FVII weekly. ABR was compared to the subjects prior ABR. Results: 5 participants have been enrolled (Median ABR 16.6; Range 12.2-26.7) (fig 2). One participant with historical ABR 26.7 has completed the study with no bleeding at 60 mg/kg MarzAA but had a spontaneous bleed 16 days into the follow-up period when no longer receiving study drug. In a participant with previously-treated but currently-untreated and uncontrolled hypertension, a fatal hemorrhagic stroke deemed unrelated to study drug occurred on Day 11. Pharmacokinetics are shown in fig 3. IV half-life of 3.5 hours was increased to SQ half-life of 9.5 hours. Levels of MarzAA at Tmax 5 hours after SQ injection were similar to levels at 6 hours after IV infusion. Median subcutaneous bioavailability was 35%; Range 32.4-37.5%. Prothrombin Time baseline of 12-12.7 seconds fell to 8-9 seconds after 18 µg/kg IV infusion (normal 9.4-12.5 seconds). Prothrombin Time gradually declined to 8.7 seconds after 7 days of 30 µg/kg SQ injection. No anti-drug antibodies have been detected to date. Conclusion: This study demonstrates that an individualized dose of daily SQ MarzAA can provide effective prophylaxis in hemophilia patients with inhibitors. Supported by Catalyst Biosciences Disclosures Levy: Catalyst Biosciences: Employment, Equity Ownership. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Biomarin: Research Funding, Speakers Bureau; Biogen: Research Funding, Speakers Bureau; Bayer: Research Funding; Amgen: Consultancy; Alnylam: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Del Greco:Catalyst Biosciences: Employment, Equity Ownership. Booth:Catalyst Biosciences: Consultancy.

Abstract: Background: The phase 3 B-LONG (adults/adolescents ≥12 years of age) and Kids B-LONG (children 〈 12 years of age) studies demonstrated the safety and efficacy of recombinant FIX Fc fusion protein (rFIXFc) for the control and prevention of bleeding episodes in subjects with severe hemophilia B (FIX levels ≤2 IU/dL). Eligible subjects from either study could continue rFIXFc treatment in the ongoing extension study, B-YOND, during which surgical procedures were allowed. Aims: To describe rFIXFc efficacy and safety in B-YOND subjects undergoing surgery. Methods: B-YOND subjects who underwent surgery received an investigator-determined rFIXFc regimen. Major surgery endpoints included rFIXFc dosing, investigator/surgeon assessment of hemostatic response (4-point scale: excellent, good, fair, poor/none), blood loss, number of transfusions, and safety. For minor surgeries, hemostatic response and dosing are summarized. Surgeries performed up to cutoff for the interim analysis (17 October 2014) were included. For safety analyses, the surgery subgroup included subjects who underwent major surgery during B-YOND and those who underwent major surgery in the parent study but had their surgical/rehabilitation period during B-YOND. Results: Fifteen major surgeries were performed in 8 subjects (7 adults/adolescents and 1 child 〈 12 years of age), most commonly orthopedic procedures (9/15 surgeries). In adults/adolescents undergoing major surgery, the median total rFIXFc dose on the day of surgery was 135.92 IU/kg (range, 60.6-317.9 IU/kg); 12 of these 14 surgeries required a single rFIXFc infusion to maintain hemostasis during surgery. The number of adults and adolescents undergoing major surgery who required an infusion decreased from Day 0 to Day 14. A single rFIXFc infusion of 99.43 IU/kg was required on the day of surgery for the single major surgery in a pediatric subject (tonsillectomy). Of 15 major surgeries, 14 surgeries were assessed for hemostatic response to rFIXFc and all were rated as excellent (n = 13, including the single pediatric surgery) or good (n = 1). Among 12 major surgeries with estimates, blood loss ranged from 0-1,000 mL intraoperatively and 0-1,000 mL postoperatively (for the single pediatric subject, blood loss was 50 mL intraoperatively and 0 mL postoperatively). One additional subject had an estimated intraoperative blood loss of 5,000 mL during liver transplantation and was the only subject who required transfusion (6 units of packed cells, 4 units of platelet concentrate, and 4 units of fresh frozen plasma intraoperatively), consistent with previously reported blood loss for this procedure in the general population (Yuasa et al. Transfusion 2005;45:879). Hemostatic response for this surgery was rated as excellent. No subject reported a bleeding episode during the postoperative/rehabilitation period. Among 12 subjects in the surgery subgroup (8 with major surgery during B-YOND; 4 with major surgery in B-LONG and a surgical/rehabilitation period during B-YOND), 3 subjects (25%) reported ≥1 adverse event (AE) during the perioperative management period. One subject who underwent major surgery experienced 2 serious AEs (anal sphincter atony and epididymitis; considered unrelated to treatment) during the perioperative management period. All AEs were assessed by the investigator as unrelated to treatment and resolved. Of 25 minor surgeries performed in 17 adults/adolescents (none in children), approximately half were dental procedures (12/25 surgeries). No rFIXFc was administered on the day of surgery for 2 minor surgeries. For the other 23 surgeries, the median number of rFIXFc infusions was 1.0 (range, 1-3) and the median total dose of rFIXFc was 79.84 IU/kg (range, 38.5-200.0). Hemostatic response was assessed in 10 of 25 minor surgeries; all were rated as excellent (n = 9) or good (n = 1). Summary/Conclusion: Hemostasis with rFIXFc during surgery was rated favorably by investigators/surgeons, with comparable blood loss to what would be expected for subjects without hemophilia. Taken together with results from the B-LONG and Kids B-LONG studies, these data indicate that rFIXFc is well-tolerated and efficacious for the management of perioperative hemostasis in individuals with severe hemophilia B. Disclosures Ozelo: Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding. Mahlangu:Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Roche: Research Funding; Amgen: Speakers Bureau. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Yuan:Biogen: Employment, Equity Ownership. Cristiano:Biogen: Employment, Equity Ownership. Mei:Biogen: Employment, Equity Ownership.