Improvement of Efficacy Outcomes in Patients Who Switched from Sucrose-Formulated rFVIII to BAY 81-8973 Prophylaxis in the LEOPOLD Clinical Trials

Background BAY 81-8973 (Kovaltry®) is a full-length, unmodified, recombinant factor VIII (FVIII), indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding and routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia A. It has the same amino acid sequence as sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). Pharmacokinetic comparisons confirmed BAY 81-8973 to have a longer half-life and lower clearance than FVIII-FS. The objective of this analysis was to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS prior to enrolling into the LEOPOLD clinical studies receiving BAY 81-8973. Methods LEOPOLD I (NCT01029340) Part B and LEOPOLD Kids (NCT01311648) were Phase 3, multinational, open-label studies that included male patients with severe hemophilia A receiving on-demand or prophylactic therapy, with ≥50 exposure days to any FVIII product and no history of FVIII inhibitors. Patients in LEOPOLD I were >12 years old and received 20-50 IU/kg BAY 81-8973 prophylaxis twice-weekly (2×W) or three times a week (3×W) for up to one year. Patients in LEOPOLD Kids were ≤12 years old and received 25-50 IU/kg BAY 81-8973 ≥2×W for six months. Dosing regimens for both studies were assigned by the investigator. In this analysis, efficacy and safety are assessed in the subset of patients in LEOPOLD I Part B and LEOPOLD Kids who were previously treated with FVIII-FS. Results In LEOPOLD I, 22 (35.5%) patients were previously treated with FVIII-FS with a median age of 27.0; in LEOPOLD Kids, 24 (47.1%) patients were previously treated with FVIII-FS with a median age of 5.0 (Table 1). In general, these switch cohorts had similar patient demographics to the whole study cohort (Table 1) and any differences did not affect the final analysis. Most patients did not change their dosing frequency when starting treatment with BAY 81-8973 but most increased their dose (FVIII-FS dose is 25 IU/kg 3×W [adults] or every other day [EOD; children]; BAY 81-8973 dose is 25-40 IU/kg 2×W or 3×W [>12 years] or 25-50 IU/kg 2×W, 3×W or EOD [≤12 years]). Switching from FVIII-FS to BAY 81-8973 resulted in lower median annualized bleeding rates (ABRs) in the LEOPOLD studies. In LEOPOLD I, median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) in the 12 months of FVIII-FS treatment prior to study entry, to 1.0 (0.0; 6.8) (Figure 1). In LEOPOLD Kids, median total ABR decreased from 3.0 (1.0; 12.0) to 2.0 (0.0; 6.0) for 0-<6 year old patients (n = 13) and from 4.0 (0.0; 10) to 0.0 (0.0; 2.1) for 6-12 year old patients (n = 11) after switching from FVIII-FS to BAY 81-8973 (Figure 1). Joint and spontaneous median ABRs were zero for <12 year old patients treated with BAY 81-8973. There were no study-drug-related adverse events (AEs) or serious AEs (SAEs) reported in patients switching from FVIII-FS to BAY 81-8973 in either LEOPOLD I Part B or LEOPOLD Kids (Table 2). One patient in the LEOPOLD Kids main study discontinued BAY 81-8973 due to a central venous catheter-related infection after six months of treatment, which was not considered study-drug-related. No FVIII inhibitors developed in any patients in either study. Conclusions Switching from FVIII-FS to BAY 81-8973 resulted in improved bleeding control in adults and children with hemophilia A and was well-tolerated. Disclosures Kenet: PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Wicklund:Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire (Takeda): Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding.

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Longitudinal Efficacy and Safety of N8-GP for Prophylaxis and Bleed Control in US Patients

Blood ◽

10.1182/blood-2021-147814 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3205-3205

Author(s):

Allison P. Wheeler ◽

Miguel A. Escobar ◽

Susan Kearney ◽

Janice M. Staber ◽

Adam R. Wufsus ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Treatment Success ◽

Efficacy And Safety ◽

Advisory Committees ◽

On Demand ◽

Routine Prophylaxis ◽

Previously Treated ◽

Extension Trial

Abstract Introduction: N8-GP is an extended half-life recombinant factor VIII product indicated for use in patients with hemophilia A. The pathfinder trials evaluated routine prophylaxis and bleed control in previously treated patients aged ≥12 years (pathfinder2) and patients aged <12 years (pathfinder5), including an extension trial (pathfinder8). The objective of the present analysis was to compare the efficacy and safety of N8-GP in US vs global (including US) patients. Methods: In the pathfinder2 trial, patients aged ≥12 years with severe hemophilia A were administered N8-GP 50 IU/kg every 4 days (Q4D) as routine prophylaxis or 20 to 70 IU/kg as on-demand treatment. Patients aged <12 years received prophylaxis with N8-GP 60 IU/kg twice weekly in the pathfinder5 trial, and bleeding episodes were treated with 20 to 75 IU/kg. In the pathfinder8 extension trial, the investigator decided on which treatment arm the patient should be allocated based on previous treatment regimen and taking into account bleeding tendency. Results: See Table for efficacy in prophylaxis (median annualized bleeding rates [ABRs]) and bleed treatment (success rate). Median ABRs tended to decrease from 0.84 (global) and 0.86 (US) in pathfinder2 to 0.00 (global) and 0.00 (US) in pathfinder8 in patients aged ≥12 years on the prophylaxis regimen. In addition, in patients aged <12 years, median ABRs decreased from 0.81 (global) and 0.76 (US) in pathfinder5 to 0.00 (global) and 0.49 (US) in pathfinder8. Treatment success rates for US patients were comparable to those for global patients across trials and 100% were rated "excellent" or "good" for patients aged <12 years in pathfinder8. Overall, there were 59 treatment-related adverse events (AEs) in patients on the prophylactic regimen in pathfinder2, 13 of which occurred in US patients, and 11 treatment-related AEs in patients treated on-demand, 3 of which occurred in US patients. In pathfinder5, there were 16 treatment-related AEs, 7 of which occurred in US patients. In pathfinder8, there were 6 treatment-related AEs in patients aged ≥12 years, 3 of which were in US patients. In addition, there was 1 treatment-related AE in a non-US patient aged <12 years. AEs included rash, redness, and injection site reactions. Across trials, 1 previously treated patient (an 18-year-old, from a US site) with an intron 22 inversion developed a low-titer inhibitor at 93 exposure days to N8-GP and was withdrawn when the titer progressed to >5 Bethesda units. The patient returned to their previous FVIII product, and their inhibitor status was negative at follow-up. Conclusions: Efficacy of N8-GP was sustained during the main and extension pathfinder trials in both global and US patients. In addition, a favorable safety profile was maintained throughout the course of the program. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Kearney: Grifols: Research Funding; Daiichi Sankyo: Research Funding; CVS Pharmacy: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Wufsus: Novo Nordisk Inc: Current Employment. Ostrow: Novo Nordisk Inc: Current Employment. Lentz: Novo Nordisk Inc: Consultancy, Honoraria, Research Funding.

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Prophylactic Dosing of Anti-Inhibitor Coagulant Complex (FEIBA) Reduces Bleeding Frequency In Hemophilia A Patients with Inhibitors: Results of the Pro-FEIBA Study

Blood ◽

10.1182/blood.v116.21.720.720 ◽

2010 ◽

Vol 116 (21) ◽

pp. 720-720 ◽

Cited By ~ 4

Author(s):

Cindy A. Leissinger ◽

Eric Berntorp ◽

Chiara Biasioli ◽

Shannon Carpenter ◽

Hyejin Jo ◽

...

Keyword(s):

Clinical Trial ◽

Allergic Reaction ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Study Drug ◽

Advisory Committees ◽

Patient Age ◽

On Demand ◽

Bleeding Episodes

Abstract Abstract 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients >2 years with a history of high-titer inhibitors who were using bypassing therapy for the treatment of bleeding episodes. Subjects on or planning immune tolerance therapy were excluded as were patients with thrombocytopenia or other bleeding disorders. This randomized, crossover study compared 6 months of AICC prophylactically dosed at 85 U/kg ± 15% on 3 nonconsecutive days per week (Prophy period) to 6 months of on-demand therapy (OD period) (target dose for the treatment of bleeds: 85 U/kg ± 15%). The 2 study periods were separated by a 3-month washout, during which time patients used on-demand therapy for bleeding. Patients were randomized to initially enter either the 6-month Prophy period or the 6-month OD period. Each patient then crossed-over to the alternate study period after a 3-month wash-out. Results: Thirty-four subjects were randomized; 26 subjects completed both study periods and were deemed evaluable per protocol (PP) for efficacy analysis of the primary outcome to compare bleeds in each 6-month treatment period. Eight subjects did not complete the study (1 patient in the Prophy treatment arm and 1 patient in the post-prophylaxis washout period died of complications associated with underlying illness and bleeding, 1 patient experienced an allergic reaction to study drug, 1 patient was lost to follow-up, and 4 patients withdrew from study). All randomized subjects were evaluated for safety. In the PP group, mean patient age was 26.9 years (median: 24.7; range: 2.8–67.9). In the total randomized group, mean patient age was 27.1 years (median: 28.7; range: 2.8–67.9). Of the 26 subjects who completed the study PP, 14 were randomized to enter the Prophy period first and then crossed-over to the OD period, while 12 subjects were initially randomized to enter the OD period and then crossed-over to the Prophy period. For the PP analysis, total bleeds and joint bleeds requiring treatment during the 2 study periods were compared (p-value is for the Wilcoxon signed-rank test of difference between OD and Prophy periods). In addition, bleeds for the 6-month period prior to enrollment were recorded retrospectively on study entry. Efficacy: Both total bleeds and joint bleeds were significantly reduced during the Prophy period as compared with the OD period (p < .0001) Table 1. There was no difference in bleed event rates based on randomization sequence (ie, no carry-over effect was detected when the Prophy period preceded the OD period). Safety: A total of 38 serious adverse events (SAEs) occurred, none of which was thrombotic in nature. One SAE was deemed by the study safety monitor to be related to the study drug (an allergic reaction). Otherwise, treatment was safe and well tolerated. Conclusion: These results in patients with hemophilia A and inhibitors show that AICC, dosed at 85 IU/kg +/− 15% given on 3 non-consecutive days each week was associated with a 62% reduction in all bleeds and a 61% reduction in joint bleeds as compared with on-demand therapy. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: This is a report of a clinical trial using the Anti-Inhibitor Coagulant Complex, FEIBA, as prophylactic therapy to prevent bleeding in hemophilia patients with inhibitors. FEIBA is not currently licensed for use in prophylaxis in the US. Berntorp:Baxter: Consultancy, Honoraria, Research Funding. Negrier:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rocino:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Windyga:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gringeri:Baxter: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria.

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Latest Results From The PUP-GCP Clinical Trial: A Low Inhibitor Rate In Previously Untreated Patients With Severe Hemophilia A Treated With Octanate

Blood ◽

10.1182/blood.v122.21.3596.3596 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3596-3596

Author(s):

Anna Klukowska ◽

Martina Jansen ◽

Vladimir Komrska ◽

Pawel Laguna ◽

Vladimir Vdovin ◽

...

Keyword(s):

Clinical Trial ◽

Rating Scale ◽

Hemophilia A ◽

Severe Hemophilia ◽

Observational Period ◽

Adverse Event Profile ◽

On Demand ◽

Previously Treated Patients ◽

Previously Treated ◽

Bleeding Episodes

Abstract Background Octanate is a highly purified, double virus inactivated, human plasma-derived factor VIII (FVIII) concentrate with all coagulation FVIII bound to its natural stabilizer VWF in a VWF:RCo/FVIII:C ratio of approximately 0.4. Five prospective GCP studies with octanate were conducted in 77 previously treated patients (PTPs) with severe hemophilia A. None of these 77 PTPs developed an inhibitor while treated exclusively with octanate. Aim To assess the immunogenicity in previously untreated patients (PUPs), a prospective clinical trial has been initiated in 2000. This included 50 PUPs with severe hemophilia A for an observational period of 100 exposure days with octanate, for at least 6 months. Methods Patients with severe hemophilia A without previous exposure to FVIII or FVIII-containing products were enrolled. Efficacy and tolerability were assessed by a 4-point verbal rating scale. Inhibitors were assessed according to modified Bethesda method prior to treatment every 3-4 exposure days (ED 1-20), and after treatment every 10 EDs (ED 21-100), but at minimum every three months. Results Two of 50 (4%) subjects developed clinically relevant inhibitor titers over the course of the study. Another two displayed inhibitors that disappeared spontaneously without change of dose or dosing interval. All inhibitors developed under on-demand treatment and before ED 50. From the 50 subjects, 42 had exceeded 50 EDs at the time of this analysis. Octanate was well-tolerated and the adverse event profile was consistent with the population studied. The hemostatic efficacy in prophylaxis and treatment of bleeding episodes was generally rated as “excellent” and no complication was reported for any surgical treatment. Conclusion Despite frequent inhibitor testing and predominant on-demand treatment, the data indicate a low overall inhibitor rate for octanate in patients who exceeded 50 exposure days (4/42) of which only 2 (4.8%) were clinically relevant. Disclosures: Klukowska: Octapharma AG: Investigator Other. Jansen:Octapharma AG: Employment. Komrska:Octapharma AG: Investigator Other. Laguna:Octapharma AG: Investigator Other. Vdovin:Octapharma AG: Investigator Other. Knaub:Octapharma AG: Employment.

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RESULTS OF AN OPEN, PROSPECTIVE, MULTICENTER, NONCOMPARATIVE STUDY OF THE PHARMACOKINETICS, EFFICACY AND SAFETY OF NONACOG ALFA IN PATIENTS AGED 6–12 YEARS WITH SEVERE AND MODERATE HEMOPHILIA B

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2020-99-6-190-198 ◽

2020 ◽

Vol 99 (6) ◽

pp. 190-198

Author(s):

T.A. Andreeva ◽

◽

V.V. Lebedev ◽

V.V. Vdovin ◽

M.A. Timofeeva ◽

...

Keyword(s):

Prophylactic Treatment ◽

Study Drug ◽

Factor Ix ◽

Hemophilia B ◽

Efficacy And Safety ◽

Open Label ◽

Time Curve ◽

Entire Study ◽

On Demand ◽

Bleeding Episodes

Providing hemophilia patients with blood coagulation preparations is one of the priority tasks of the national health care system. In 2011, the first recombinant factor IX was created in Russia (rFIX, nonacog alpha, Innonafactor, GENERIUM JSC), that was previously studied for pharmacokinetic (PK) parameters, efficacy and safety in adult patients and adolescents over 12 years of age with severe and moderate hemophilia B. Objective of this open-label, prospective, multicenter, noncomparative clinical study was to study PK, efficacy and safety of Innonafactor in 12 patients aged 6 to 12 years with severe and moderate forms of hemophilia B (FIX activity less than 2%). The study included periods of screening, studies of PK parameters and treatment within 26±1 weeks, but not less than 50 days of administration of the studied drug. Nonacog alfa was administered in the study of PK parameters at a dose of 75 IU/kg, once, for prophylactic treatment – at a dose of 45±10 IU/kg, 2 times a week with an interval of 72–96 h. 30 minutes after administration of the studied drug, FIX activity increased to 73,93±13,35%, with a gradual decrease to 5,88±1,97% 72 hours after administration. The area under the «concentration ‒ time» curve in the section 0–72 h (AUC0–72) and with exponential extrapolation to infinity (AUC00‒∞) was 1573,41±407,16%*h and 1808,74 ± 437,59%*h respectively. Biological half-life (T1/2) was 28,11±8,60 hours. During preventive treatment there were 19 hemorrhagic episodes, 14 (74%) bleedings were post-traumatic and 5 (26%) bleedings were spontaneous. Mean number of bleeding episodes over the entire observation period was 1,9±1,4. Mean number of episodes of spontaneous bleeding that occurred within 72 hours after Innonafactor administration in patients with bleeding was 2,5±2,1. During the entire study period, patients received 942,5 thousand IU of the drug Innonafactor, 890,5 thousand IU were administered for prophylaxis and 52 thousand IU to stop bleeding on demand. Mean single dose of Innonafactor for prophylactic treatment was 46,24±5,86 IU/kg, for on-demand treatment – 49±13,1 IU/kg. Of the 19 registered bleeding episodes, 14 (73.7%) episodes required the administration of the studied drug; 5 (26,3%) bleedings stopped on their own. To stop one episode of bleeding, an average of 2,3±2,3 administration of nonacog alfa was required. At the end of the study, the proportion of hemophilia B patients with residual FIX activity of 2% or more was 92%. During the study, 14 adverse events (AEs) were registered in 7 (58,3%) patients. All reported AEs were not study drug related and did not require study drug withdrawal. Thromboembolic complications and immunogenic reactions were not registered. Thus, the data obtained indicate efficacy and safety of Innafactor both for prophylactic treatment and for on-demand treatment of bleeding in patients aged 6 to 12 years with severe and moderate hemophilia B.

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Surgery with Turoctocog Alfa: Efficacy and Safety in Bleeding Prevention During Surgical Procedures - Results From the guardian™ Trials.

Blood ◽

10.1182/blood.v120.21.2228.2228 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2228-2228

Author(s):

Elena Santagostino ◽

Steven R. Lentz ◽

Mudi Misgav ◽

Brigitte Brand ◽

Pratima Chowdary ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Efficacy And Safety ◽

Advisory Boards ◽

Surgical Bleeding ◽

Previously Treated Patients ◽

Previously Treated ◽

Hemostatic Efficacy ◽

The Guardian ◽

Extension Trial

Abstract Abstract 2228 Introduction: Novo Nordisk is developing turoctocog alfa, a human third generation recombinant FVIII for treatment of hemophilia A. During the pivotal trial in adult and adolescent previously treated patients with severe hemophilia A (guardian™1), subjects in need of surgery were able to participate in a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding. Pediatric (<12 years of age) previously treated patients in the guardian™3 trial were allowed to undergo minor surgery if needed during the trial. In addition, after completing these initial trials subjects were allowed to continue treatment with turoctocog alfa in the extension trial (guardian™2) which also includes a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding. Methods: We here describe surgeries performed within the guardian trials. For the ongoing guardian™2 extension trial, only cases included in the interim analysis (data cut-off 21NOV2011) are included. Results: In all, results from 10 major and 3 minor surgeries are included. Surgery indication was related to hemophilia joint disease in 8/13 cases. The hemostatic efficacy during and after surgery was rated on a 4-point scale (excellent, good, moderate and none) by the Investigator and/or Surgeon. Details and outcome of the individual surgeries performed are presented in Table 1. In addition, there were no safety concerns. Discussion: Prevention of surgical bleeding is an important aspect of hemophilia treatment. In the present 13 surgeries, including all surgeries performed with turoctocog alfa in the phase 3 guardian™ trials, hemostatic efficacy during and after was rated as either excellent or good in each case. The results support that turoctocog alfa has an excellent safety and efficacy profile for use in hemophilia A. Disclosures: Santagostino: Novo Nordisk and Pfizer: Research Funding; Pfizer, Baxter, Bayer, CSL Behring, Kedrion, Grifols and Novo Nordisk: Consultancy; Bayer, Baxter, Pfizer, CSL Behring, Novo Nordisk, Biotest, Kedrion and Grifols: Speakers Bureau. Lentz:Novo Nordisk: Consultancy, Research Funding. Brand:Bayer: Travel support, Travel support Other; Novo Nordisk, Baxter, Pfizer: Advisory Boards, Advisory Boards Other; Novo Nordisk: Honoraria. Chowdary:Novo Nordisk: Consultancy. Savic:Novo Nordisk: Speakers Bureau. Lindblom:Novo Nordisk A/S: Employment.

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RESULTS OF THE OPEN MULTICENTER PROSPECTIVE CLINICAL STUDY OF THE EFFICACY, SAFETY, AND PHARMACOKINETICS OF MOROCTOCOG ALPHA IN 6 TO 12 YEAR OLD CHILDREN WITH HEMOPHILIA A

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2021-100-2-236-245 ◽

2021 ◽

Vol 100 (2) ◽

pp. 236-245

Author(s):

M.A. Timofeeva ◽

◽

T.A. Andreeva ◽

V.V. Vdovin ◽

A.N. Mamaev ◽

...

Keyword(s):

Clinical Study ◽

Drug Administration ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Study Drug ◽

Drug Dose ◽

Severe Hemophilia ◽

Efficacy And Safety ◽

Spontaneous Bleeding ◽

On Demand

Currently, the main method of treatment for hemophilia A is replacement therapy with drugs of blood coagulation factors VIII (FVIII). As a result of the development of new production technologies, recombinant FVIII are increasingly used for the treatment of hemophilia A. The justification for the use of new drugs in pediatric clinical practice requires careful preparation and clinical research studies of their efficacy and safety. The aim of this study was to evaluate the efficacy, safety and pharmacokinetics (PK) of domestic B-domain deleted recombinant factor VIII of Moroctocog alpha (Octofactor, GENERIUM JSC) in a cohort of children with hemophilia A aged 6 to 12 years in the framework of phase III clinical study of moroktocoga alpha in children 2 to 12 years old with hemophilia A. Materials and methods of the research: the age cohort of 6 to 12 years olds of an open multicenter prospective noncomparative study included 27 male children with severe hemophilia A (mean age 8,3±1,9 years). The study was carried out sequentially in 2 stages. Stage I included the study of PK parameters in 22 patients after a single study drug dose of 50 IU/kg. At stage II, the efficacy and safety of the drug was assessed in patients of stage I, as well as in additionally included 5 patients who received the study drug dose of 30±10 IU/kg per day every 2–3 days for 22±1 weeks of treatment. To assess the efficacy, we analyzed the incidence of spontaneous bleeding that occurred within 48–72 h after drug administration; the number of injections and the dose of FVIII used for prophylaxis, as well as for treatment on demand of one episode of bleeding, taking into account its severity; number of patients with severe hemophilia A with residual FVIII activity >/=1% 48–72 h after drug administration; the investigator's overall assessment of response to therapy on the acute hemarthrosis response scale. The main indicators for the analysis of PK properties were the area under the «concentration-time» curve, the half-life, the elimination constant, the increase in activity, and the degree of recovery of activity. To assess safety, the frequency of formation of an inhibitor to FVIII, the dynamics of vital and laboratory parameters, the frequency and characteristics of adverse events (AEs) associated with the administration of the drug were taken into account. Results: the area under the FVIII-time activity curve in the region of 0–48 h (AUC0-48) and with exponential extrapolation to infinity (AUC0-inf) was 731,82±264,94%*h and 756,11±270,16%*h, respectively. The half-life (T1/2) was 10,32±2,27 hours. In the examined age group, 78 bleeding were recorded, of which only 27 (35%) were spontaneous, including 24 (30%) episodes that occurred during 48–72 hours after the administration of drug under investigation. Haemorrhage within 48–72 hours after administration of the Octofactor drug was absent or was observed rarely (1–3 times) against the background of prophylactic treatment in most patients (88%), the median number of bleeding within 48–72 hours after administration of the study drug was 2 episodes per observation period. The proportion of spontaneous bleeding was the smallest in patients receiving a single prophylactic doses of the study drug 2000–3000 IU (7% of all bleeding), the largest proportion of spontaneous bleeding was observed in patients receiving a single prophylactic doses of the study drug 1000–2000 IU (70% of bleeding). The average single dose of Octofactor for preventive treatment was 1290,4±458,6 IU or 39,12±7,79 IU/kg, for on-demand treatment – 1641,7±722,4 IU per single injection. Of the 78 reported bleeding episodes, 68 (87%) required the study drug administration for relief, while the remaining 10 bleedings were selfcontained. On average, to stop bleeding, it took 1,5±0,8 injections of the drug on demand, median doses were 1 [1; 2], and average doses were 2434,3±1501,7 IU. During the study, 37 AEs were recorded in 15 (56%) patients. At the same time, 36 AEs (97%) were not associated with the drug under investigation, and one AE (allergic reaction), according to the researchers, was associated with the use of the drug. Thus, the analysis of data indicates the efficacy and safety of the Octofactor drug both the prophylactic treatment and treatment of on-demand bleeding in 6 to 12 year old patients with severe hemophilia A.

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The Crimson 1 Study: A Phase 3 Study to Evaluate the Efficacy and Safety of Subcutaneous Marzeptocog Alfa (activated) for on-Demand Treatment and Control of Bleeding Episodes in Subjects with Hemophilia A or Hemophilia B, with Inhibitors

Blood ◽

10.1182/blood-2020-137806 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Linda Neuman ◽

Shraddha Desai ◽

Tom Knudsen ◽

Frank Del Greco ◽

Howard Levy

Keyword(s):

Initial Dose ◽

Hemophilia A ◽

Factor Vii ◽

Coagulation Disorder ◽

Efficacy And Safety ◽

Publicly Traded ◽

Phase 3 ◽

On Demand ◽

History Of ◽

Bleeding Episodes

Background Hemophilia A (HA) and HB are X-linked bleeding disorders caused by a deficiency of Factor VIII (HA) or Factor IX (HB). A significant number of individuals with HA and HB develop inhibitors against the wild-type FVIII or FIX, respectively, and thereby become refractory to factor replacement treatment. Treatment of episodic bleeding in these individuals requires technical expertise to gain the requisite intravenous (IV) access and is often associated with pain. This causes delays in administration, which results in prolonged bleeding and accumulation of blood in the joint or other bleeding site. Currently approved FVIIa containing products take 6-24 hours to achieve hemostasis and maintain efficacy. Marzeptacog alfa (activated) (MarzAA), a novel variant activated recombinant Factor VII (rFVIIa), is being developed for subcutaneous (SQ) administration to address this important unmet need. Data from the Phase 1 study, MAA-102, demonstrated that SQ MarzAA is quickly absorbed and has the potential to achieve and maintain plasma levels in the desired range with an acceptable safety profile. This open-label, global, multi-center, randomized, cross-over Phase 3 study will evaluate the efficacy and safety of MarzAA for on demand treatment of spontaneous or traumatic bleeding episodes in adolescents and adults with congenital HA or HB with inhibitors. MarzAA will be compared to the Standard of Care (SOC). Approximately 60 subjects will be enrolled at 54 sites in 19 countries. Study Design and Methods Key inclusion criteria: Eligible male or female subjects ≥ 12 years of age must have: confirmed diagnosis of HA or HB unresponsive to or intolerant of standard replacement therapy; history of bleeding with annualized bleeding rate of ≥ 8; investigator-confirmed subject's ability to identify bleeding episodes and administer MarzAA SQ and infuse SOC IV at home. Key exclusion criteria: Subjects should not have had previous exposure to SQ administration of rFVIIa or exposure to any other variant rFVIIa; known positive antibody or hypersensitivity to MarzAA, FVIIa, or variants thereof; history of other coagulation disorder(s); platelet count <50,000/µL; CD4 T cell count <200 cells/mm3. Treatment: Subjects >17 years of age will be randomized in blocks to target treatment of approximately 5 bleeds with MarzAA and an additional 5 bleeds with SOC in either order, Sequence A or Sequence B, with a washout period to assess anti-drug antibodies (ADA) status between treatments. A total of 488 eligible bleeds will be treated, ~244 bleeds with each treatment, until ≥80% of patients have ≥3 bleeds treated with MarzAA and SOC. Pharmacokinetic samples will be collected during the MarzAA treatment period. Subjects 12-17 years of age will be enrolled after a positive DSMB assessment of 30 eligible bleeds treated with MarzAA. Subjects will administer 60 µg/kg SQ dose of MarzAA, at 3-hour intervals, for up to 3 doses as required to achieve hemostasis. Endpoints: Primary endpoint includes percentage of treated bleeds resulting in effective hemostasis (excellent or good) at 24 hours after the initial dose. Key secondary endpoints include time to cessation of bleeding after the initial dose; percentage of treated bleeds resulting in effective hemostasis at fixed timepoints; percentage of those that maintain hemostasis at 48 hours after the initial dose; use and amount of rescue therapy. Key safety endpoints include the incidence of adverse events; occurrence of thrombotic events and binding and/or neutralizing anti-drug antibodies. Key exploratory endpoints include assess patient satisfaction with the Treatment Satisfaction Questionnaire for Medicine- 9; assessment of pain using the Visual Analogue Scale; time required to administer treatment. Statistics: The goal is to demonstrate the true proportion of bleeds effectively treated with MarzAA is not inferior to SOC. Using a baseline efficacy of 85% for SOC, with a -12% margin of non-inferiority, treatment of 244 bleeds in each group provides 90% power with a one-sided 2.5% significance level to substantiate this result. Figure Disclosures Neuman: Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Desai:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Knudsen:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Del Greco:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company. Levy:Catalyst Biosciences: Current Employment, Current equity holder in publicly-traded company.

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Pharmacokinetics, Efficacy and Safety of BAX326, a Novel Recombinant Factor IX: A Prospective, Controlled, Multicenter Study in Previously Treated Patients with Severe (FIX Level < 1%) or Moderately Severe (FIX Level ≤ 2%) Hemophilia B.

Blood ◽

10.1182/blood.v120.21.2222.2222 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2222-2222

Author(s):

Jerzy Windyga ◽

Toshko Lissitchkov ◽

Oleksandra Stasyshyn ◽

Vasily Mamonov ◽

Luminita Rusen ◽

...

Keyword(s):

Research Funding ◽

Prophylactic Treatment ◽

Hemophilia B ◽

Control Group ◽

On Demand ◽

Previously Treated ◽

Bleeding Episodes ◽

The Mean ◽

Hemostatic Efficacy ◽

Level 2

Abstract Abstract 2222 Hemophilia B is a congenital X-linked bleeding disorder whose severity is associated with diminished or absent levels of circulating FIX. Treatment with regular prophylactic FIX infusions has significant medical and quality of life benefits by maintaining adequate plasma levels of FIX for hemostasis approximating a non-diseased state. BAX326 nonacog gamma is a novel recombinant FIX (rFIX) that is manufactured without the addition of any materials of human or animal origin, and viral inactivation/reduction is achieved through solvent/detergent (S/D) treatment as well as 15nm nanofiltration. Pharmacokinetics, hemostatic efficacy and safety of BAX326 were assessed in a prospective clinical trial in patients aged 12 to 65 years with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B, previously treated with plasma-derived and/or recombinant FIX concentrates. PK parameters were compared with a commercially-available rFIX used as an active control in a crossover design. Hemostatic efficacy of BAX326 administered twice weekly as prophylaxis was compared with a historical control group treated on-demand. A total of 86 patients were enrolled and 73 were treated with BAX326. All subjects treated had previous exposure to a FIX concentrate for ≥ 150 days prior to entry into the study. Subjects included in the PK analysis (n=28) received one 75 ± 5 IU/kg infusion with BAX326 and one infusion with commercial rFIX in random order prior to receiving prophylactic treatment at a dose range from 40 to 60 IU/kg two times a week with BAX326. An additional 31 subjects also received prophylactic treatment (21–67 exposure days), and 14 subjects received BAX326 on-demand (5–25 exposure days). More than 70% of subjects had 50 or more exposure days to BAX326 during the study. PK equivalence between BAX326 and the comparator rFIX was confirmed as the 90% confidence intervals of the ratio (BAX326/comparator rFIX) of the geometric mean of AUC 0–72 h/dose (1.063 [1.03; 1.09]) was fully contained in the margins for equivalence (0.8 to 1.25). The mean half-life (T1/2) of BAX326 was 26.70h ± 9.55, and incremental recovery (IR) was 0.87 ± 0.22 IU/dL: IU/kg. Repeated PK analysis after 6 months of prophylactic treatment confirmed the results of the initial values. Twice weekly prophylactic treatment with BAX326 was effective in preventing bleeding episodes, with a significantly lower (79%, p<0.001) annualized bleed rate (ABR) during prophylaxis (mean ABR 4.20) compared to an on-demand treatment in a historical control group (mean ABR 20.0). Among the 56 subjects on prophylaxis, 24 subjects (43%) did not bleed; the mean ABR for joint bleeds was 2.79, and 1.70 for spontaneous bleeds. Of 238 total acute bleeds, 201 (84.4%) were controlled with 1–2 infusions of BAX326. Hemostatic efficacy at resolution of bleed was rated excellent or good in 95.4% of all treated bleeding episodes. The efficacy as related to degree of severity of bleeding episodes was excellent or good in 96.8 % of minor bleeds, 95 % of moderate bleeds and 92.9 % of major bleeding episodes. BAX326 was safe and well-tolerated, with similar adverse reaction rates to the comparator rFIX. The safety assessments demonstrate the safety and tolerability of BAX326 in patients with moderately severe or severe hemophilia B. There were no product related SAEs, no inhibitory or binding FIX antibodies, no antibodies to CHO, and no allergic reactions or thrombotic events; AEs considered related to BAX326 (dysgeusia and pain in extremity) were transient and mild, and occurred with an overall incidence of 2.7%. There were no treatment-related AEs within 24 hours after infusion. Elevated pre- and post-infusion values for thrombogenic markers (TAT, F1.2 and D-dimer) in some subjects did not reveal any pattern indicative of clinically relevant thrombogenicity with either BAX326 or the comparator rFIX, and were not associated with AEs. These data indicate that BAX326 is safe and efficacious in treating bleeding episodes and in routine prophylaxis in patients aged 12 years and older with hemophilia B. None of the historical risk factors, such as hypersensitivity reactions, inhibitor formation or thrombotic events were observed and few related adverse events occurred. Disclosures: Windyga: Baxter: Research Funding. Lissitchkov:Baxter: Research Funding. Stasyshyn:Baxter: Research Funding. Mamonov:Baxter: Research Funding. Rusen:Baxter: Research Funding. Lamas:Baxter: Research Funding. Oh:Baxter: Employment. Chapman:Baxter: Employment. Fritsch:Baxter: Employment. Pavlova:Baxter: Employment. Wong:Baxter: Employment. Abbuehl:Baxter: Employment.

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Efficacy and Safety of BAY 94-9027 (Damoctocog Alfa Pegol) Prophylaxis in Patients with Severe Hemophilia a and Comorbidities: A Post Hoc Analysis of PROTECT VIII Data

Blood ◽

10.1182/blood-2019-128486 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1117-1117

Author(s):

Wolfgang A. Miesbach ◽

Giovanni Di Minno ◽

Elena Santagostino ◽

Dr. Klamroth ◽

Inga Bayh ◽

...

Keyword(s):

Risk Factors ◽

Hiv Infection ◽

Research Funding ◽

Hemophilia A ◽

Hcv Infection ◽

Efficacy And Safety ◽

Main Study ◽

Post Hoc Analysis ◽

On Demand ◽

Post Hoc

Background: The availability of factor (F)VIII replacement products has dramatically improved life expectancy for patients with hemophilia A (HA). However, older patients face distinct challenges. Age-related comorbidities such as cardiovascular disease (CVD), often involving treatments that can increase the risk of bleeding, and patients who received treatment before the advent of recombinant products, are more likely to have been exposed to blood-borne viruses carrying chronic infections. It is important to understand clinical outcomes with FVIII products in patients with HA and these comorbidities. BAY 94-9027 (damoctocog alfa pegol; Jivi) is a B-domain deleted recombinant FVIII, site-specifically PEGylated with a 60 kDa (2×30 kDa) polyethylene glycol to extend its half-life. Efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe HA were demonstrated in the phase II/III PROTECT VIII trial and its Extension. This post hoc analysis assessed bleeding rates and safety outcomes for prophylaxis patients in PROTECT VIII and its Extension, based on the presence or absence of comorbidities of interest. Patients/Methods: PROTECT VIII (NCT01580293) was a partially randomized, open-label trial of 134 males aged 12-65 years with severe HA (FVIII <1%) and ≥150 FVIII exposure days. Prophylaxis patients (n=114) received BAY 94-9027 25 IU/kg twice weekly (2×W) for a 10-week run-in period. Patients with ≤1 spontaneous joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days or 60 IU/kg every 7 days for the main 26-week study; patients enrolling after the randomization arms were full, or with ≥2 bleeds in the run-in period, received 30-40 IU/kg 2×W. Patients completing the main study could enter an extension, continuing BAY 94-9027 on any regimen used in the main study. Baseline characteristics, annualized bleeding rates (ABR) and safety were examined for patients on prophylaxis treatment during main study and its Extension with and without comorbidities of interest. Comorbidities included human immunodeficiency virus (HIV) infection, hepatitis B or C infection (HBV or HCV), and risk factors for CVD (hypertension, hypercholesterolemia, hypertriglyceridemia and hyperlipidemia). Results: A total of 104 patients who received BAY 94-9027 prophylaxis during the main study and the Extension (data cut-off: Jan 2018) were included in this analysis. Mean (SD) age of patients was 34.3 (13.0) years with a median (Q1;Q3) of 7 (2;15) bleeds in the 12 months before enrolment. Most patients (72.1%) had target joint(s) at baseline. Before study, 22 (21.2%) patients were receiving on-demand treatment; the remaining 82 were on regular prophylaxis. Most patients (n=66, 63.5%) had ≥1 comorbidity of interest. Of those, chronic HCV infection (HCV detection, asymptomatic) was most common (40/66, 60.6%), followed by acute HCV infection (HCV detection, symptomatic, 26/66, 39.4%), HBV infection (20/66, 30.3%), hypertension (17/66, 25.8%), hyperlipidemia (7/66, 10.6%), HIV infection (5/66, 7.6%), and hypertriglyceridemia (2/66, 3.0%). Patients with comorbidities of interest were older (mean age: 41.5 vs 21.9 years, respectively) and had a higher median (Q1;Q3) number of joint bleeds in the previous 12 months (5 [1;12] vs 3 [0;10], respectively) than patients without comorbidities (n=38). Pre-study, median ABR was 6.0 and 7.0 in patients with and without comorbidities of interest respectively, which decreased to 2.9 and 1.5 respectively during the main study, and further to 1.8 and 1.2 respectively during the Extension (Figure). In all patients with comorbidities of interest, robust improvements in median ABR were observed between the 12-month pre-study period and the main study period, and were maintained or improved in the Extension. Patients with comorbidities of interest had similar numbers of drug-related adverse events (AEs; 10.6% vs 23.7%), serious AEs (39.4% vs 28.9%) and discontinuations due to AEs (1.5% vs 2.6%) than those without comorbidities of interest during main study and Extension. Conclusions: The majority of patients (63.5%) in PROTECT VIII had ≥1 comorbidity of interest. The results from this post hoc analysis indicate that long-term BAY 94-9027 prophylaxis provided excellent control of bleed rates and was well tolerated in patients with severe HA and comorbidities of interest: HIV, HBV or HCV infection or risk factors for CVD. Figure Disclosures Miesbach: Biotest: Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Freeline: Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Grifols: Speakers Bureau; Biomarin: Consultancy, Honoraria; LFB: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; UniQure: Consultancy, Honoraria, Research Funding; CSL: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Bayer: Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Di Minno:Sanofi: Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Kedrion: Speakers Bureau; CSL: Speakers Bureau; Pfizer: Speakers Bureau; Novo Nordisk: Speakers Bureau. Santagostino:Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Spark: Speakers Bureau; Kedrion: Consultancy, Speakers Bureau; Bioverativ: Consultancy, Speakers Bureau; UniQure: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire: Consultancy, Speakers Bureau; CSL: Consultancy, Speakers Bureau; Sanofi: Speakers Bureau. Klamroth:Bayer, Biomarin, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, Takeda: Consultancy; Bayer, Novo Nordisk, SOBI: Research Funding. Bayh:Bayer: Employment. Soto:Bayer: Employment. Hermans:LFB: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; CAF-DCF: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; CSL: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Kedrion: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau.

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Improved Bleeding Outcomes in Patients Who Switched From Sucrose-Formulated rFVIII to BAY 94-9027 Prophylaxis in PROTECT VIII

Blood ◽

10.1182/blood-2020-137565 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Mark Reding ◽

Thomas Moulton ◽

Erika Soltes Rak ◽

Mindy L Simpson

Keyword(s):

Single Dose ◽

Adverse Events ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Main Study ◽

On Demand ◽

Study Enrollment ◽

Previously Treated ◽

To Receive

Background BAY 94-9027 (damoctocog alfa pegol; Jivi®) is a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life compared with standard-half-life FVIII products, including sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). A previous pharmacokinetic study confirmed longer half-life and lower clearance with a single dose of BAY 94-9027 compared with a single dose of FVIII-FS. The phase 2/3 PROTECT VIII study (NCT01580293) demonstrated the efficacy, safety and utilization of BAY 94-9027 as prophylactic and on-demand therapy for adolescents and adults with severe hemophilia A, including during major and minor surgeries. This post hoc subgroup analysis of PROTECT VIII aimed to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS as FVIII replacement therapy prior to study enrollment. Methods In PROTECT VIII, 134 patients were treated with BAY 94-9027 for the main, 36-week study period. Patients with ≤1 breakthrough bleed during a 10-week run-in period treated with BAY 94-9027 25 IU/kg twice-weekly (2×W) prophylaxis were considered eligible for randomization and were thus randomized to receive BAY 94-9027 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the 26-week study period. Patients with >1 bleed, and thus ineligible for randomization (IFR), and those eligible for randomization but enrolled after randomized arms were full (EFR), were assigned to a 30-40 IU/kg 2×W regimen (Figure 1). In total, 114 patients received BAY 94-9027 prophylaxis and 20 patients were treated on-demand. Patients who completed the main study could enter into an optional extension, in which they could continue to receive BAY 94-9027 on any PROTECT VIII study regimen. This present analysis was designed to assess annualized bleeding rates (ABR), adverse events and FVIII utilization of a subset of PROTECT VIII patients who were previously treated with prophylaxis or on-demand FVIII-FS. Pre-study ABRs were based on patient recall of bleeding events during the 12 months prior to study entry. Results Of the 114 patients who received BAY 94-9027 prophylaxis in the PROTECT VIII main study period, 38 (33.3%) patients were previously treated with FVIII-FS (29 received prior prophylaxis, 9 received prior on-demand treatment) (Table 1). Of these, 8 (21%), 19 (50%) and 11 (29%) patients were treated with 2×W (n = 4 IFR; n = 4 EFR), E5D and E7D BAY 94-9027 regimens in PROTECT VIII, respectively. For patients treated with either prophylactic or on-demand FVIII-FS treatment in the 12-month pre-study period and who were eligible for randomization, median total and joint ABRs decreased during Weeks 10-36 with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens (Figure 2). In the 29 patients who switched from FVIII-FS prophylaxis regimens only prior to PROTECT VIII study entry, median (Q1; Q3) total ABRs also decreased from 7.0 (1.0; 14.0) pre-study to 0.0 (0.0; 2.1), 2.1 (0.0; 4.2), and 4.3 (0.0; 5.7) with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens, respectively. Median joint ABRs also decreased in patients who were previously treated with prophylaxis regimens only with FVIII-FS, from 3.5 (0.0; 8.5) pre-study to 0.0 (0.0; 2.1), 1.1 (0.0; 4.0), and 2.2 (0.0; 5.7) with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens during the main study period, respectively. The median dose of BAY 94-9027 administered per infusion in patients who switched from either on-demand or prophylaxis regimens of FVIII-FS was 38.7 IU/kg. One patient who switched from FVIII-FS discontinued BAY 94-9027 during PROTECT VIII due to an acute, resolved, hypersensitivity episode occurring after the start of the first infusion; no study-drug-related serious adverse events were reported. Overall, of patients who were treated with FVIII-FS in the 12 months prior to PROTECT VIII study enrollment, BAY 94-9027 was well-tolerated and the safety profile was similar to that of the overall prophylaxis patient population in PROTECT VIII (Table2). Conclusions Prophylaxis with BAY 94-9027 resulted in lower median total and joint ABRs compared with prior prophylaxis or on-demand treatment with FVIII-FS, resulting in improved efficacy with a similar safety profile. Disclosures Reding: Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; BioMarin: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Simpson:HEMA Biologics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bioverativ/Sanofi: Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Consultancy, Honoraria.

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