This study will enroll children who have hemophilia A with inhibitors who successfully completed immune tolerance induction per the ISTH criteria (negative inhibitor titer, recovery \>66% of expected, and half-life of \>6 hours with their current FVIII concentrate). Previous to emicizumab, there was only one option for these patients which was to continue FVIII therapy in a prophylaxis mode to prevent bleeding. There was a sense that the ongoing FVIII served to maintain tolerance however no evidence for this notion exists and in fact what limited data is available suggests that continuing FVIII may not be necessary simply to maintain tolerance.

To figure out this question, this will be a randomized, controlled 2 arm study which will randomize patients post-successful ITI to emicizumab plus weekly FVIII (for maintenance of tolerance) versus emicizumab alone. Patients will be followed for up to 2 years. We aim to enroll 52 subjects. The FVIII weekly arm can use any factor VIII concentrate and emicizumab is standard of care for inhibitor and non-inhibitor patients.

The objective was to undertake an early cost-effectiveness assessment of valoctocogene roxaparvovec (valrox; Roctavian) compared to factor (F)VIII prophylaxis or emicizumab (Hemlibra; Roche HQ, Bazel, Switzerland) in patients with severe Hemophilia A (HA) without FVIII-antibodies. We also aimed to incorporate and quantify novel measures of value such as treatment durability, maximum value-based price (MVBP) and break-even time (ie, time until benefits begin to offset upfront payment). We constructed a Markov model to model bleeds over time which were linked to costs and quality-of-life decrements. In the valrox arm, FVIII over time was estimated combining initial effect and treatment waning and then linked to bleeds. In FVIII and emicizumab arms, bleeds were based on trial evidence. Evidence and assumptions were validated using expert elicitation. Model robustness was tested via sensitivity analyses. A Dutch societal perspective was applied with a 10-year time horizon. Valrox in comparison to FVIII, and emicizumab showed small increases in quality-adjusted life years at lower costs, and were therefore dominant. Valrox' base case MVBP was estimated at €2.65 million/treatment compared to FVIII and €3.5 million/treatment versus emicizumab. Mean break-even time was 8.03 years compared to FVIII and 5.68 years to emicizumab. Early modeling of patients with HA in The Netherlands treated with valrox resulted in estimated improved health and lower cost compared to prophylactic FVIII and emicizumab. We also demonstrated feasibility of incorporation of treatment durability and novel outcomes such as value-based pricing scenarios and break-even time. Future work should aim to better characterize uncertainties and increase translation of early modeling to direct research efforts.

This study will evaluate if Eloctate is superior to Emicizumab in reducing inhibitors in children with severe hemophilia when given before the first bleed (preemptive) and continued weekly to prevent bleeds (prophylaxis); and whether Eloctate immune tolerance induction (ITI) plus emicizumab is superior to Eloctate ITI alone in eradicating inhibitor formation in children and adults with severe hemophilia A.

Background: Inhibitor development is the most serious treatment-related complication of replacement coagulation factor VIII (FVIII) therapy for patients with haemophilia A. Immune tolerance induction (ITI), which involves intensive and prolonged treatment with plasma-derived or recombinant FVIII, is the only clinically proven strategy for eradication of inhibitors. The bispecific antibody emicizumab is approved for use in patients with and without inhibitors to prevent bleeding but does not eliminate inhibitors. MOTIVATE (www.motivate-study.com) aims to capture different approaches to the treatment and management of patients with haemophilia A and inhibitors, document current ITI approaches from real-world clinical experience, and evaluate the efficacy and safety of ITI, emicizumab prophylaxis and ITI with emicizumab prophylaxis. Methods: The investigator-initiated MOTIVATE study [ClinicalTrials.gov identifier: NCT04023019; EudraCT 2019-003427-38] will investigate in real-life clinical practice the management of patients with haemophilia A of any severity who have developed inhibitors to FVIII. All treatment is at the investigator’s discretion. The following treatment approaches will be evaluated: Group 1 – ITI with Nuwiq®, octanate® or wilate® and aPCC/rFVIIa if needed to treat bleeding episodes (BEs) or during surgery or for prophylaxis; Group 2 – ITI with Nuwiq®, octanate® or wilate® and emicizumab prophylaxis and aPCC/rFVIIa if needed to treat BEs or during surgery; Group 3 – routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI and aPCC/rFVIIa if needed to treat BEs or during surgery. Patients will not be randomised to a treatment group and may change groups during the study. Conclusions: It is planned to enrol 120 patients who will be followed for up to 5 years. Optional sub-studies will explore factors that may influence ITI results as well as the impact of different treatment approaches on important aspects of patient health, including joint and bone health and the risk of thrombotic events.

This is a single arm, phase 4, prospective, open-label, United States single-center study to determine the hemostatic characteristics of Hemlibra (emicizumab) as measured by coagulation laboratory parameters in the mild hemophilia A male patient population with endogenous altered FVIII (baseline FVIII activity of \>5% to 30%). The safety and hemostatic efficacy of Hemlibra (emicizumab) in this patient population will be investigated. Secondary outcomes will assess changes in joint health and quality of life in treated patients.

INTERVENTION:

investigational material(s) Generic name etc : ACE910 INN of investigational material : emicizumab Therapeutic category code : 634 Human blood preparations Dosage and Administration for Investigational material : Single subcutaneous or intravenous administration of ACE910 control material(s) Generic name etc : ACE910 INN of investigational material : emicizumab Therapeutic category code : 634 Human blood preparations Dosage and Administration for Investigational material : Single subcutaneous administration of ACE910

CONDITION:

Hemophilia

A PRIMARY OUTCOME:

safety; bioavailability; pharmacokinetics; laboratory tests

SECONDARY OUTCOME:

pharmacodynamics; Laboratory tests

INCLUSION CRITERIA:

Japanese healthy males aged 20‐44 years, inclusive

Background: Factor VIII (FVIII) is protected by binding to its carrier protein, von Willebrand factor (VWF) in the circulation. VWF contributes to hemostasis particularly under high shear flow condition by extending its multimeric configuration. By contrast, coagulation factors including FVIII are thought to play a dominant role under low shear. Since FVIII binds to VWF unlike other coagulation factors, FVIII may contribute to thrombus formation even under high shear conditions. FVIII has to be released from VWF and activated to exert its coagulation function. However, the role of interaction between FVIII and VWF on hemostasis under flow conditions needs to be explored in addition to the protective function of VWF. Aims: To analyze the mechanism and role of FVIII and VWF interaction on hemostasis under flow conditions. Methods: Whole blood samples were obtained from patients with type 2A von Willebrand disease (VWD). FVIII, VWF, FVIII/VWF (final concentration; f.c. 1U/mL), FVIII plus ESH8 (f.c. 1 μM), and emicizumab (ACE910; f.c. 100 μg/mL) were added to the blood followed by perfusion into the collagen-coated flow chamber under controlled high (2,500s ) and low (50s ) shear conditions. ESH8 is an anti-FVIII antibody that interrupts the release of FVIII from VWF, and emicizumab is a bispecific antibody mimicking activated FVIII (FVIIIa). The concentration of emicizumab was chosen, as it was the highest dose in clinical study. After the perfusion, formed thrombus was fixed and immunostaining was performed to visualize platelets, VWF, thrombin, and FVIII. Thrombi were observed by using confocal laser scanning microscopy and the obtained images were analyzed by Image Pro Premier 3D. Initial thrombus formation was measured as surface coverage (SC) and thrombus development was measured as thrombus volume (TV). Results: SC and TV were impaired in VWD particularly under high shear (high: SC 8.3%, TV 3.9x103μm3 , low: SC 2.7%, TV 2.9x103μm3 ). Addition of FVIII/VWF improved thrombus formation to normal level under both shear conditions (high: SC 37.3%, TV 2.4x104 μm3 , low SC 4.3%, TV 4.1x103 μm3 ). Addition of VWF improved SC and TV under both shear conditions (high: 40.9%, 1.7x104 μm3 , low: SC 3.0%, TV 3.3x103 μm3 ), suggesting that the VWF function was crucial under both shear. By contrast, addition of FVIII alone did not improve SC and TV under both shears (high: SC 9.9%, TV 5.0x103 μm3 , low: SC 2.4%, TV 3.1x103 μm3 ). Since FVIII/VWF had a greater effect on TV than VWF alone, FVIII enhanced thrombus development under high shears, however, this effect required the presence of VWF. FVIII immunostaining demonstrated the binding of FVIII on platelet surface in the FVIII-added experiment and, therefore, FVIII binding alone was not sufficient to initiate coagulation. Since FVIII may need to be activated on the platelet surface in a timely fashion, it was speculated that the optimal delivery from VWF and activation of FVIII on platelets was required for hemostasis. To analyze the role of FVIII and VWF interaction on hemostasis under flow condition, ESH8 was used to modify FVIII/VWF binding by blocking FVIII release. Treatment of FVIII/VWF with ESH8 did not change SC but slightly impaired TV under high shear (high: SC 41.8%, TV 1.8 x103 μm3 ). Thus, the presence of FVIII at thrombus was not enough and the release of FVIII from VWF and presumably activation of FVIII on the platelet surface might be essential for thrombus formation under high shear. Under low shear, both SC and TV were interrupted by ESH8 (SC 2.6%, TV 3.1x103 μm3 ), suggesting the important role of FVIII and coagulation under low shear. Lastly, to analyze the impact of activated FVIII on thrombus formation under flow conditions, emicizumab was evaluated in this system. In contrast to FVIII, emicizumab alone improved thrombus formation (high: SC 26.0%, TV 1.1 x103 μm3 , low: SC 3.5%, TV 4.2 x103 μm3 ). The rate of improvement in SC and TV was better under low shear than high shear, which implicated the coagulative role of emicizumab. Even under high shear, however, emicizumab enhanced thrombus formation. Therefore, the role of emicizumab in substituting for the activated form of FVIII might be able to rapidly initiate coagulation even under high shear. Conclusion: VWF delivers and releases FVIII in a timely fashion on platelet surface. FVIII has to become active on platelets for hemostasis and FVIIIa can accelerate thrombus formation even under high shear condition.

This is a multi-center randomized phase III clinical trial, the Inhibitor Prevention Trial, in which Eloctate will be compared with Emicizumab, using adaptive design, to prevent inhibitors in patients with severe hemophilia A.

This is a multi-center randomized phase III clinical trial, the Inhibitor Eradication Trial, in which Eloctate ITI plus Emicizumab will be compared with Eloctate ITI alone to eradicate inhibitors in severe hemophilia A.

Introduction: Investigational non-factor products such as ACE 910 (emicizumab) potentially offer new treatment for hemophilia patients with inhibitors. However, their unregulated mechanisms of action raise questions regarding safety and efficacy in specific clinical contexts. As an antibody to FIX(a) and FX(a), ACE 910 lacks the inherent regulatory characteristics for hemostasis present in replacement factor and bypassing agents. A phase III study of emicizumab (NCT02622321) is ongoing in hemophilia A patients with inhibitors. To evaluate the treatment options for those experiencing breakthrough bleeding, we studied the in vitro thrombin generation (TG) profile of various combinations of FEIBA or recombinant (r) FVIIa and a biosimilar version of emicizumab (BSEm). FEIBA has been used over 40 years to treat and prevent bleeding episodes in hemophilia A and B patients with inhibitors, and shown to be safe and highly effective. Recombinant FVIIa has been available to clinicians since 1996 and has a sound safety record. Methods: BS-Em expressed in mammalian cells, purified, and biochemically characterized was analyzed in standard TG experiments using plasma from individual inhibitor patients. Therapeutic doses of BS-Em (20-600 nM) combined with various concentrations of FEIBA (0.05-1 U mL -1) and rFVIIa (0.88-5.25 μg mL-1) were tested. A normal TG range was established using plasma from healthy individuals. Results: The reference range for peak thrombin levels in healthy individuals was 47-144 nM. Both rFVIIa and FEIBA showed an add-on effect on TG in combination with BS-EM. The combination of rFVIIa (1.75 μg mL-1) and BS-Em (600 nM) induced a 2.2- fold increase in peak thrombin, but did not reach the reference range. However, the antibody-FEIBA combination (600 nM BS-Em + 0.5 U mL -1 FEIBA) reached peak thrombin values of >400 nM, representing an ∼10-fold increase over BS-EM alone. FEIBA concentrations above 0.25 IU mL-1 combined with 600 nM BS-Em induced peak thrombin values up to 5-fold of normal. Discussion/Conclusion: These in vitro experiments demonstrate the potential for suboptimal hemostatic effect following co-administration of rFVIIa and BS-Em, and excessive thrombin generation after co-administration of FEIBA and BS-Em at antibody concentrations expected to occur in patients participating in the ongoing study. Therefore, careful judgment will be required when treating breakthrough bleeds in patients receiving emicizumab.