Use of Emicizumab in Patients with Hemophilia a with and without Inhibitors: A Single Center Experience

Emicizumab is a humanized bispecific recombinant monoclonal antibody that binds the enzyme factor IXa and the substrate factor X and mimics the function of FVIII. It solved some unmet needs of haemophilia A (HA) treatment, such as regimen (once weekly up to once monthly infusion) and route of administration (subcutaneous). Most importantly, emicizumab reduce bleeding episodes and improved the quality of life of these patients. Emicizumab received FDA approval for prophylaxis in HA patients with inhibitors in November 2017 and for patients without inhibitors in October 2018.The aim of this study is to provide information on treatment with emicizumab in patients with severe haemophilia A with and without inhibitors in terms of efficacy, safety and quality of life. Here we report our experience with 9 patients with severe haemophilia A (5 with inhibitors and 4 without inhibitors) that were switched from replacement therapy to emicizumab prophylaxis. Median age at initiation of treatment was 26.8 years for patients with inhibitors and 18.7 years for those without inhibitors. Median duration of therapy was 12 months for patients with inhibitors and 8 months for those without inhibitors. All patients were started on emicizumab with a loading dose of 3 mg/kg once weekly for 4 weeks followed by a maintenance dose of 1.5 mg/kg once weekly or every two weeks. The mean annual bleeding rates (ABR) in patients without inhibitor prior to emicizumab was 1.5 compared to 0 while on emicizumab prophylaxis. In subjects with inhibitors ABR was 1.8 compared to 0.4 while on emicizumab prophylaxis. Furthermore, no adverse events including thrombotic events occurred in course of emicizumab prophylaxis. Bleeding events in course of emicizumab prophylaxis did not request any treatment with replacement therapy or bypassing agents. The questionnaire evaluating quality of life (HAL v 2.0 - 2015 ITA; pedHAL v 2.0 - 2015 ITA) was administered to the patients before switch to emicizumab and after a follow up of six months. The scores showed a significant improvement in terms of quality of life in course of emicizumab prophylaxis. In conclusion, our experience suggests that emicizumab prophylaxis is safe and improved protection against bleeding and quality of life compared to replacement therapy in patients with severe A haemophilia. Disclosures Di Raimondo: Amgen: Honoraria; Jazz Pharmaceutical: Honoraria; Pfizer: Honoraria; Janssen Pharmaceuticals: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria.

Prophylactic Treatment of Severe Haemophilia Á Patients with Inhibitors to FVIII with Peglip-FVIII

Background: FVIII replacement therapy is ineffective for severe haemophilia A (HA) patients who develop inhibitors to FVIII. Patients with intractable inhibitors currently require FVIII mimetics and/or bypassing agents to prevent bleeding. PEGylated liposomes (PEGLip) have been shown to protect FVIII from anti-FVIII antibodies in ex-vivo human studies and in combination with FVIII may present an option for the prophylactic treatment of inhibitor patients. Aims: To (a) demonstrate that PEGLip-FVIII administered intravenously (IV) to severe HA patients with history of inhibitors to FVIII enhances their clotting activity, (b) compare the number of bleeding episodes before and after PEG-Lip treatment, and (c) demonstrate that PEGLip-FVIII is well tolerated with no increase in inhibitor titres. Methods: Stage A: Four patients with a history of inhibitors were given single IV injections of PEGLip-FVIII (simoctocog alfa) at a dose of 22mg/kg PEGLip + 35 IU/kg FVIII and assessed for clotting activity at 0 hours (pre-injection) and at 20min, 1, 2, 4, 8, 24 hours, and daily thereafter up to 7 days using Rotational Thromboelastometry. Stage B: Patients received IV injections of PEGLip-FVIII for 6-weeks at a frequency determined by the investigator based on results obtained during Stage A. Inhibitor titres were monitored throughout. Results: Results are shown below. Treatment with PEGLip-FVIII was highly tolerated with no clinically significant changes in inhibitor titres. No Adverse Drug Reactions were reported. The mean frequency of administration of PEGLip-FVIII was every 5.7±1.4 days. The mean number of bleeding episodes reported during Stage B was 0.5±0.9 per month (due to 1 patient) compared with 0.9±0.4 per month recorded during the 24 weeks prior to enrollment. Conclusion: PEGLip-FVIII in inhibitor patients demonstrated efficacy in preventing spontaneous bleeds without increasing inhibitor titres, indicating a novel FVIII-based treatment for this cohort. Planned studies in a larger cohort may confirm our findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Efficacy and Safety of Recombinant Factor IX-FIAV and Bypassing Agents in Thrombin Generation Analyses in Hemophilia A Patient Plasma: The FIVITAS Study

Factor (F)IX-FIAV, a FIX variant with four amino acid substitutions that functions independently of the cofactor VIIIa, has been previously shown to ameliorate the hemophilia A (HA) phenotype in vivo [Quade-Lyssy et al. J. Thromb. Haemost. 2014]. Here we evaluated the efficacy of purified recombinant FIX-FIAV in severe, moderate, and mild hemophilia A patient plasma employing thrombin generation and intrinsic clotting activity (aPTT) analyses. The combination of FIX-FIAV with current hemophilia A therapeutics was used for preclinical safety assessment. Plasma was obtained from 21 HA patients, seven per HA phenotype, with a median age of 38 years [interquartile range (IQR) 27.5 - 49.5]. The plasma levels of FIX, FX, prothrombin, and antithrombin of all included patients were within the normal range. To determine the effect of FIX-FIAV on FXIa-triggered thrombin generation parameters (lag time, endogenous thrombin potential (ETP)), plasma was spiked with 100% (5 µg/ml in severe/mild) or 125% (6 µg/ml in moderate) FIX-FIAV prior to analysis. FIX-FIAV significantly shortened the lag time in all patient plasmas irrespective of disease severity (Figure 1) with an overall median of 4.4 min [IQR 3.6 - 6.9] in the absence of FIX-FIAV vs. 3.1 min [IQR 2.4 - 4.5] in the presence of FIX-FIAV (p<0.0001, Table 1). Similar observations were obtained following aPTT analyses: median clotting time of 115.5 sec [IQR 105 - 173.9] without vs. 97.7 sec [IQR 91.8 - 136.2] with 100% FIX-FIAV (p = 0.0039). Conversion of the thrombin generation lag time to FVIII-like activity using a FVIII calibration for each individual patient plasma revealed that FIX-FIAV mitigated the HA phenotype from severe to moderate, from moderate to mild, and from mild to normal (Table 1). Interestingly, following the addition of FIX-FIAV a minor but significant decrease in ETP was observed for non-severe HA patient plasma (p = 0.016 for mild and p = 0.016 for moderate), while FIX-FIAV increased the median ETP in severe HA plasma by 2.1-fold (p = 0.22) (Figure 2, Table 1). This may result from competition between the added FIX-FIAV and endogenous FIX for interaction with residual functional FVIII. In line with this, experiments performed in the presence of an anti-FVIII antibody that inhibits FVIII activity significantly enhanced the ETP in all patient plasmas (p = 0.016 for each individual severity, Figure 2) in addition to shortening the lag time (Figure 1). Next, we evaluated the combination of FIX-FIAV with bypassing agents (1 IU/mL aPCC or 1.5 mg/mL rFVIIa) in nine patient plasmas, three per phenotype. Addition of aPCC or rFVIIa to FIX-FIAV-spiked plasma did not significantly affect aPTT clotting times nor ETP values in comparison to adding aPCC or rFVIIa only, respectively. The median lag time shortened significantly, albeit modestly, for the combination of FIX-FIAV with aPCC in comparison to conditions with aPCC only: 5.2 min [IQR 3.0 - 6.4] vs. 5.5 min [IQR 3.6 - 7.7], p = 0.0078, respectively. Similar findings were obtained when combining FIX-FIAV with rFVIIa relative to rFVIIa only: median lag time 4.9 min [IQR 2.2 - 6.1] vs. 5.3 min [IQR 3.3 - 8.8], p = 0.0039. Hence, no substantial synergistic effect was observed when combining FIX-FIAV with bypassing agents aPCC or rFVIIa for HA. In contrast, combining approximate hemostatic levels (55 µg/ml) of emicizumab, a bispecific antibody mimicking FVIIIa, with FIX-FIAV resulted in a ~1.1-fold reduced lag time and ETP relative to emicizumab alone (p = 0.016 and p = 0.004 respectively). This is suggestive of a minor synergistic procoagulant effect, which is consistent with the FIX(a)-FX(a) bridging capacity of emicizumab. In conclusion, FIX-FIAV could serve as a potential treatment for hemophilia A as it mitigates the hemophilia A phenotype in patient plasma, also in the presence of an inhibitory anti-FVIII antibody. While further safety assessment is warranted, no severe procoagulant effects were observed for the combination of FIX-FIAV with conventional hemophilia A therapeutics. Figure 1 Figure 1. Disclosures Romano: Swedish Orphan Biovitrum B.V.: Other: Travel grant and aforementioned Research Funding in the form of the Young Investigator's Award 2020, Research Funding. Liu: uniQure Biopharma B.V.: Current Employment. McCreary: uniQure Biopharma B.V.: Ended employment in the past 24 months. Leebeek: Roche: Other: DSMB member of a study sponsored by Roche; uniQure Biopharma B.V.: Consultancy, Research Funding; Swedish Orphan Biovitrum B.V.: Other: Travel support, Research Funding; Biomarin: Consultancy; CSL Behring: Consultancy, Research Funding; Shire/Takeda: Consultancy, Research Funding. Bos: VarmX B.V.: Research Funding; uniQure Biopharma B.V.: Research Funding.

Costs of the management of hemophilia A with inhibitors in Spain

Introduction: Emicizumab is a first-in-class monoclonal antibody, recently authorized for the treatment of hemophilia A with inhibitors. This study aims to estimate the direct and indirect costs of the management of hemophilia A with inhibitors, in adult and pediatric patients, including the prophylaxis with emicizumab. Methods: We calculated the costs of the on-demand and prophylactic treatments with bypassing agents (activated prothrombin complex concentrate and recombinant activated factor VII) and the emicizumab prophylaxis, from the societal perspective, over 1 year. The study considered direct healthcare costs (drugs, visits, tests, and hospitalizations), direct non-healthcare costs (informal caregivers), and indirect costs (productivity loss). Data were obtained from a literature review and were validated by an expert group. Costs were expressed in 2019 euros. Results: Our results showed that the annual costs of the prophylactic treatment per patient varied between €543,062.99 and €821,415.77 for adults, and €182,764.43 and €319,826.59 for children, while on-demand treatment was €532,706.84 and €789,341.91 in adults, and €167,523.05 and €238,304.71 in pediatric patients. In relation to other prophylactic therapies, emicizumab showed the lowest costs, with up to a 34% and 43% reduction in the management cost of adult and pediatric patients, respectively. It reduced the bleeding events and administration costs, as this drug is less frequently administered by subcutaneous route. Emicizumab prophylaxis also decreased the cost of other healthcare resources such as visits, tests, and hospitalizations, as well as indirect costs. Conclusion: In comparison to prophylaxis with bypassing agents, emicizumab reduced direct and indirect costs, resulting in cost savings for the National Health System and society.

Expert opinion on the UK standard of care for haemophilia patients with inhibitors: a modified Delphi consensus study

Background and Aims: Despite advances in haemophilia care, inhibitor development remains a significant complication. Although viable treatment options exist, there is some divergence of opinion in the appropriate standard approach to care and goals of treatment. The aim of this study was to assess consensus on United Kingdom (UK) standard of care for child and adult haemophilia patients with inhibitors. Methods: A modified Delphi study was conducted using a two-round online survey. A haemophilia expert steering committee and published literature informed the Round 1 questionnaire. Invited participants included haematologists, haemophilia nurses and physiotherapists who had treated at least one haemophilia patient with inhibitors in the past 5 years. Consensus for 6-point Likert scale questions was pre-defined as ⩾70% participants selecting 1–2 (disagreement) or 5–6 (agreement). Results: In all, 46.7% and 35.9% questions achieved consensus in Rounds 1 ( n = 41) and 2 ( n = 34), respectively. Consensus was reached on the importance of improving quality of life (QoL) and reaching clinical goals such as bleed prevention, eradication of inhibitors and pain management. There was agreement on criteria constituting adequate/inadequate responses to immune tolerance induction (ITI) and the appropriate factor VIII dose to address suboptimal ITI response. Opinions varied on treatment aims for adults and children/adolescents, when to offer prophylaxis with bypassing agents and expectations of prophylaxis. Consensus was also lacking on appropriate treatment for mild/moderate patients with inhibitors. Conclusion: UK healthcare professionals appear to be aligned on the clinical goals and role of ITI when managing haemophilia patients with inhibitors, although novel treatment developments may require reassessment of these goals. Lack of consensus on prophylaxis with bypassing agents and management of mild/moderate cases identifies a need for further research to establish more comprehensive, evidence-based treatment guidance, particularly for those patients who are unable/prefer not to receive non-factor therapies.

Recombinant porcine FVIII for bleed treatment in acquired hemophilia A: findings from a single-center, 18-patient cohort

Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired autoantibodies to endogenous factor VIII (FVIII) decrease FVIII activity and lead to a bleeding phenotype. A substantial majority of individuals who develop AHA present with severe bleeding. Effective treatment requires both immunosuppressive therapy and prompt hemostatic treatment. Bleeding is commonly treated with bypassing agents (BPAs) such as recombinant activated FVII (rFVIIa) or activated prothrombin complex concentrates Disadvantages to BPAs include the inability to monitor response with standard laboratory assays, inconsistent hemostatic efficacy, and thrombosis. Recombinant porcine FVIII (rpFVIII: Obizur, Baxter, Deerfield, IL) was approved by the US Food and Drug Administration (FDA) for bleed treatment in AHA in 2014, and has the advantage of laboratory monitoring of FVIII activity levels and known hemostatic efficacy in the presence of anti-human FVIII inhibitors and after failure of BPAs. Using an algorithm-based approach, rpFVIII has been used to successfully treat 18 patients with AHA at our center with substantially lower doses than the current FDA-recommended dosing. Additionally, data from our cohort show that the preexposure anti-porcine Bethesda titer does not reliably predict the clinical response to rpFVIII treatment and is not correlated with the anti-human Bethesda titer. We also present data showing lower total rpFVIII use for initial bleed resolution when rpVIII is used upfront, as compared with use as rescue therapy. We validated our dosing algorithm, which uses much lower than FDA-recommended doses with 14 more patients than in our previously reported patient series.