Emicizumab Treatment Research Articles

Cost-effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti-FVIII inhibitors in France.

The development of an anti-FVIII inhibitor is the most serious complication of haemophilia A occurring in up to 30% of severe haemophilic patients. The current management of haemophilia A with inhibitor uses bypassing agents (BPA) and represents a significant therapeutic burden together with a limited adherence to prophylactic treatment. Emicizumab is the first monoclonal antibody developed in haemophilia A approved for the prevention of bleeding episodes in patients with anti-FVIII inhibitor. The purpose of this study is to evaluate the incremental cost-effectiveness ratio (ICER) of emicizumab versus BPAs. A Markov model was developed over a five-year time horizon to estimate the comparative costs and benefits of the different therapeutic approaches in this rare disease. Model inputs were clinical, including annual bleeding rate and quality of life, and economical including mainly costs of prophylaxis, bleeds and adverse events. Emicizumab treatment is dominant, ie lest costly and more effective, in the base-case analysis saving 234191 € for a gain of 0.88 QALY. This is confirmed by both the deterministic and probabilistic sensitivity analyses. The main limit of the study remains the absence of long-term clinical data allowing to relate treatment consumption to clinical benefit, especially in the progression of haemophilic arthropathy. Our results show that emicizumab is a cost-effective treatment allowing to consider an easy to implement prophylactic treatment for haemophilia A patients with anti-FVIII inhibitors.

Real-World Persistence with and Adherence to Emicizumab Prophylaxis in Persons with Hemophilia a: A Secondary Claims Database Analysis

Introduction: Emicizumab is a subcutaneously administered, humanized bispecific monoclonal antibody, approved for routine prophylaxis in persons with hemophilia A (PwHA) with or without factor VIII inhibitors. Little is known about patterns of emicizumab use in clinical practice. We aimed to evaluate real-world persistence with and adherence to emicizumab treatment for PwHA on prophylaxis. Methods: This retrospective study used de-duplicated commercial insurance claims data from IBM® MarketScan® Commercial Research and IQVIA PharMetrics® Plus databases from 16 November 2017 to 31 December 2019. Individuals included met the following criteria: 1) evidence of emicizumab use (at least two prescription fills) and 2) continuous enrollment for at least three months pre-emicizumab initiation. Individuals were followed until the end of study period or continuous enrollment. Persistence was defined as the proportion of individuals continuing treatment with emicizumab during the study period. Time to discontinuation and proportion of individuals who restarted emicizumab prophylaxis were reported for patients who discontinued emicizumab. Discontinuation was defined as 60 days without a prescription fill. Adherence was measured over the post-index persistence period using the proportion of days covered (PDC), and the proportion of individuals adherent at ≥80% PDC threshold was reported. Results: We identified 328 unique individuals who met the inclusion criteria. All patients were male (100%); the average age was 23 years (standard deviation [SD] ±16; range=1-64); and the average follow-up post-index was eight months (245±147 days). The vast majority of individuals (92%) were persistent with emicizumab prophylaxis during the study period. Among those who discontinued emicizumab (n=25), the average time to discontinuation was approximately three months (84±124 days); 40% restarted emicizumab prophylaxis after discontinuation, with an average time to restart of approximately four months (126±56 days). During the period for which individuals were persistent to treatment, adherence to emicizumab was high (81%); with 70% individuals meeting the ≥80% PDC threshold. Among those with at least one-year post-index enrollment (n=48), adherence during the first year was also high (85%), with 77% individuals adherent at the ≥80% PDC threshold. Conclusions: In this study, the vast majority of individuals treated with emicizumab had high rates of adherence and persistence to treatment. This is one of the first studies to report real-world persistence with and adherence to emicizumab prophylaxis in PwHA. Future evaluations should examine the association of persistence and adherence with health outcomes in this population. Disclosures Mahajerin: Spark Therapeutics, Alexion, Genentech, Inc.: Speakers Bureau. Khairnar:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Meyer:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Abbass:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Wang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Acumen, LLC: Ended employment in the past 24 months. Lee:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Tzeng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Raimundo:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company.

Emicizumab treatment: Impact on coagulation tests and biological monitoring of haemostasis according to clinical situations (BIMHO group proposals).

Emicizumab, a bispecific humanised monoclonal antibody restoring to some extent the function of activated FVIII deficient in haemophilia A, represents a major therapeutic advance in the management of haemophilia A patients. No dosage adjustment is required, which leads to a major change for patients used to regular biological monitoring which is particularly burdensome in the case of substitution therapy. In some circumstances, such as before an invasive procedure or in case of bleeding, biological monitoring will be necessary and emicizumab's interference with haemostasis tests, particularly those based on an activated partial thromboplastin times (aPTT), must be known to best interpret the tests and to select the most appropriate methods to guide therapy. The normalisation of aPTT in patients treated with emicizumab is not sufficient to consider haemostasis as normalised. In the event of administration of FVIII to a patient receiving emicizumab, the determination of FVIII should use a chromogenic method using non-human reagents. Coagulation global tests have been proposed to evaluate the biological response when using bypassing agents in patients treated with emicizumab, but the usefulness must be confirmed. The French group BIMHO presents proposals for biological monitoring of a patient treated with emicizumab according to clinical situations.

Emicizumab treatment and monitoring in a paediatric cohort: real-world data.

Real-world data on emicizumab use and monitoring in paediatric severe haemophilia A (HA) patients are scarce. We therefore sought to evaluate safety, efficacy, and laboratory monitoring of emicizumab prophylaxis in a cohort of 40 children with severe HA, including 22 non-inhibitor patients and nine infants younger than one year. Bleeding, trauma, adverse events, and surgeries were documented during a median follow-up of 45weeks. Emicizumab levels, activated partial thromboplastin time (aPTT) values, and thrombin generation were measured before and during therapy. Twenty patients experienced zero bleeds. All bleeding was trauma-related, and bleeding risk was positively correlated with the length of emicizumab prophylaxis. Sixteen surgical interventions were performed in 12 patients, with no thrombotic complications or thrombotic microangiopathy. Prolonged aPTT values normalised after emicizumab initiation, correlating with an increase in emicizumab plasma levels. Elevation in the thrombin generation was observed following emicizumab prophylaxis, with lower values recorded in younger infants. Emicizumab prophylaxis was safe and well tolerated. As all bleedings were trauma-related, laboratory monitoring could not predict bleeding risk. Our results do not support routine thrombin generation monitoring in children treated by emicizumab, yet further studies are warranted in the context of surgical procedures.

Cost-Effectiveness and Budget Impact of Emicizumab Prophylaxis in Haemophilia A Patients with Inhibitors.

Recent evidence demonstrated that weekly prophylaxis with subcutaneous bispecific antibody (emicizumab) has shown higher efficacy in adolescent and adults patients affected by haemophilia A (HA) with inhibitor, compared with patients treated on demand or on prophylaxis with bypassing agents (BPAs). However, no economic evaluations assessing the value and sustainability of emicizumab prophylaxis have been performed in Europe. This study assessed the cost-effectiveness of emicizumab prophylaxis compared with BPA prophylaxis and its possible budget impact from the Italian National Health Service (NHS) perspective. A Markov model and a budget impact model were developed to estimate the cost-effectiveness and budget impact of emicizumab prophylaxis in HA patients with inhibitors. The model was populated using treatment efficacy from clinical trials and key clinical, cost and epidemiological data retrieved through an extensive literature review. Compared with BPAs prophylaxis, emicizumab prophylaxis was found to be more effective (0.94 quality adjusted life-years) and cost saving (-€19.4/-€24.4 million per patient lifetime) in a cohort of 4-year-old patients with HA and inhibitors who failed immune tolerance induction. In the probabilistic sensitivity analysis, emicizumab prophylaxis had always 100% probability of being cost-effective at any threshold. Further, the use of emicizumab prophylaxis was associated to an overall budget reduction of €45.4 million in the next 3 years. In conclusion, the clinically effective emicizumab prophylaxis can be considered a cost-saving treatment for HA with inhibitor patients. Furthermore, emicizumab treatment is also associated to a significant reduction of the health care budget, making this new treatment a sustainable and convenient health care option for Italian NHS.

Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline.

The factor VIII mimetic emicizumab (Hemlibra, Hoffman-la Roche, Basel, Switzerland) has a novel mode of action that affects the laboratory monitoring of patients receiving this treatment. This guideline from the United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO) aims to provide advice for clinical and laboratory staff on appropriate use of laboratory assays in patients with Haemophilia A treated with emicizumab. The guideline was prepared by a review of the available literature and discussion and revision by the authors. The guideline describes the effect of emicizumab on commonly used coagulations tests and provides recommendations on the use of assays for measurement of factor VIII and factor VIII inhibitor in the presence of emicizumab. The guideline also provides recommendations on measurement of emicizumab. Knowledge of the effect of emicizumab on coagulation tests and factor assays is required to ensure appropriate testing and monitoring of therapy in patients receiving this drug.

Patterns and Predictors of Emicizumab Adherence in People with Hemophilia

Introduction: Emicizumab is a subcutaneously administered, humanized bispecific monoclonal antibody that is recently approved for hemostatic prophylaxis in people with hemophilia A (PWH) with or without factor VIII inhibitors. We hypothesize that the new route and frequency of administration would lead to better treatment adherence compared to factor or bypass products in PWH outside of clinical trials. We performed the current study to test the hypothesis and to examine potential predictors of non-adherence associated with emicizumab treatment. Methods: We performed a retrospective cohort study at the Washington Center for Bleeding Disorders. Inclusion criteria included PWH with moderate to severe hereditary hemophilia (FVIII <5%), clinician recommendation for routine prophylaxis, receipt of clinical care and medication from a hemophilia treatment center (HTC), at least 12 months of prior exposure to factor or bypass products, and at least 3 months of emicizumab treatment. For patients who were previously enrolled in emicizumab clinical trials, adherence data were collected from the time of first commercial product administration. Adherence percentage (%) was estimated as days of drug dispensed / days elapsed x 100 and non-adherence % was determined as 100 - adherence %. Relevant patient, condition, treatment, and socioeconomic variable data were collected from review of medical records. To assess the difference in drug adherence, we compared the adherence % of emicizumab versus that of factor or bypass product in the same patients using the paired t test. To assess predictors of non-adherence %, we used a generalized linear model (GLM) with log link and gamma distribution to account for the right skewed distribution of the outcome. A multivariable GLM was built to incorporate the most significant predictors of non-adherence. Results: We identified 56 PWH that initiated commercial emicizumab from 1/2018 to 5/2019 at our HTC. Five patients were excluded for fewer than 3 months of follow-up on treatment and 3 patients were excluded for not having prior exposure to factor therapy. The remaining 48 patients had a median duration on emicizumab of 7 months (IQR 5-9) at the time of study. The most common dosing frequency was weekly administration (77%). The median age at treatment index date was 17 years (IQR 9-36), 65% were Caucasian, and 46% had Medicaid or Medicare insurance. The majority of patients had a diagnosis of severe hemophilia (90%), 42% had a history of inhibitor (15% active inhibitor), and 25% were previously enrolled in an emicizumab interventional trial. Prior to emicizumab initiation, 46% of patients had 5 or more self-reported annualized bleeds. The most common reason for emicizumab initiation was patient preference (35%), followed by breakthrough bleeding (33%), difficult venipuncture (21%), and shortened factor half-life (10%). Among 12 patients who previously received only on demand treatment, their adherence on emicizumab was 89%. Among 36 patients who previously received routine prophylaxis, their adherence was significantly higher on emicizumab (98%) than factor/bypass products (89%) (p=0.002). Specifically, 18 out of 48 patients (38%) had factor/bypass adherence <75% (or refused prophylaxis) and 2 out of 48 patients (4%) had emicizumab adherence <75%. Various factors were associated with increased emicizumab non-adherence (Table 1). Age group had the strongest association where young and older adult PWH had more non-adherence % than children and adolescents (Figure 1). On multivariable analysis, age group, active inhibitor, and prior factor/bypass agent non-adherence (episodic or <75% usage) were significantly associated with increased emicizumab non-adherence. Conclusions: In the current study, we found that PWH requiring routine prophylaxis were more likely to be adherent to emicizumab than previous factor or bypass agents. Age group (young adult), active inhibitor, and prior non-adherence to factor product were significant predictors for decreased emicizumab adherence but the differences were small. Given the long half-life of the drug, the significance of non-perfect adherence on bleeding outcomes needs to be studied prospectively with longer clinical follow-up. Disclosures No relevant conflicts of interest to declare.

PRO57 COST MINIMIZATION ANALYSIS OF EMICIZUMAB IN THE PROPHYLAXIS OF INHIBITOR-NEGATIVE PATIENTS WITH HEMOPHILIA A IN TURKEY

The aim of this study is to conduct a cost minimization analysis (CMA) of prophylactic treatment of Emicizumab in inhibitor-negative patients with hemophilia A compared to prophylactic and episodic treatments with pdFVIIIs or rFVIIIs from the perspective of the national reimbursement agency (SSI) in Turkey. The study was conducted based on HAVEN3 clinical trial, which was designed to model the treatment of inhibitor-negative Hemophilia A patients. A cost minimization model was developed in Microsoft Excel®. In the base case analysis, Emicizumab prophylaxis was compared to prophylactic and episodic FVIII treatments. Probability of developing inhibitors to FVIII during Emicizumab treatment was calculated as 0,45% per year and included in the costs. The costs associated with the complications that may occur in patients with hemophilia A and the adverse events reported in the HAVEN3 trial were added to the direct costs. All direct medical costs were included in the model from SSI perspective considering a calendar year. Calculations were made in TRY and reported after converting into Euro (1€=6,67 TRY; 2 May 2019). While the average direct cost per patient per year was calculated as €106.981,20 with Emicizumab prophylaxis for the treatment of inhibitor-negative patients with hemophilia A, it was calculated as €117.140,70 with FVIII prophylaxis and €404.385 with episodic treatment. Compared to episodic treatment (€ -297.404) and prophylactic treatment (€ -10.160) with FVIII, Emicizumab prophylaxis is found to be a less costly treatment option and to be a cost-minimizing treatment. Prophylactic treatment of Emicizumab for inhibitor-negative patients with hemophilia A is a less costly treatment and is an option to reduce the cost burden to SSI compared to other treatments.

Spotlight on emicizumab in the management of hemophilia A: patient selection and special considerations.

Emicizumab is a factor (F)VIIIa-mimicking bispecific antibody recognizing FIXa and FX molecules. In the phase 1/2 clinical studies, once-weekly subcutaneous administration of emicizumab has shown a favorable safety profile with encouraging efficacy in the patients with hemophilia A (PwHA) irrespective of the presence of anti-FVIII inhibitors. Moreover, in the following phase 3 studies, emicizumab treatment by once-weekly, bi-weekly or tetra-weekly administration have been still well-tolerated, but some thromboembolic events or thrombotic microangiopathy were observed associated with the concomitant use of activated prothrombin complex concentrates (aPCC) for breakthrough bleeds. Since approved for routine prophylaxis in PwHA in the US, EU, and Japan, a compass on patient selection for emicizumab treatment and special considerations on the practical situations such as concomitant treatment by bypassing agents (BPAs) or clotting factor concentrates (CFCs) with less thrombotic risk, inhibitor eradication by immune tolerance induction (ITI) should be provided. There is no doubt that emicizumab is an alternate first-line therapy for any existing BPA as hemostatic treatment for PwHA with inhibitor, but we should be more cautious in combination with aPCC on breakthrough bleeds under emicizumab prophylaxis because of thrombotic risk. For severe PwHA without inhibitor, since most patients are under CFCs prophylaxis, switching from CFCs to emicizumab should be considered when the advantage of emicizumab prophylaxis surpasses that of CFCs prophylaxis from the viewpoint of hemostatic effect by treatment, physical activity according to the life stage, health condition of the joints, adherence and complication. There are pros and cons on the timing of introduction of emicizumab for cases scheduled to start ITI or cases of ongoing ITI. Introduction of emicizumab to previously untreated patients and nonsevere PwHA without inhibitor is also required to discuss in consideration of risk of inhibitor development and unforeseen safety issues.

Every 2 Weeks or Every 4 Weeks Subcutaneous Injection of Emicizumab in Pediatric Patients with Severe Hemophilia A without Inhibitors: A Multi-Center, Open-Label Study in Japan (HOHOEMI Study)

Introduction: Emicizumab is a novel, subcutaneously injectable, recombinant humanized bispecific monoclonal antibody which mimics the function of activated coagulation factor VIII. Due to its mechanism of action and lack of sequence homology, emicizumab is not expected to induce or be affected by anti-factor VIII (FVIII) antibodies (inhibitors). Emicizumab once-weekly dosing has been approved for hemophilia A patients with inhibitors of all ages in several countries. A clinically meaningful prophylactic effect and favorable safety of emicizumab given every 2 weeks (Q2W) and every 4 weeks (Q4W) in adult/adolescent patients has been demonstrate in HAVEN3 study (NCT02847637) and HAVEN4 study (NCT03020160). This is the first report to assess emicizumab prophylaxis in pediatric patients without inhibitors including a patient previously untreated with FVIII.Methods: The present study (JapicCTI-173710) enrolled Japanese patients aged <12 years with hemophilia A without inhibitors. Patients received a loading dose of 3 mg/kg weekly for the first 4 doses, followed by a maintenance dose of 3 mg/kg Q2W or 6 mg/kg Q4W. This interim analysis was performed after at least 6 patients in each dosing cohort had completed at least 12 weeks of treatment with emicizumab prophylaxis.Results: A total of 13 male patients were enrolled in 2 cohorts. The numbers of patients aged 0 - < 2, 2 - < 6, and 6 - < 12 years were 1, 2, and 3 in the Q2W cohort and 2, 2, and 3 in the Q4W cohort. All patients had been previously treated with FVIII prophylaxis except for 1 patient aged 4 months in the Q4W cohort who was previously untreated. As of the data cutoff date of March 14, 2018, the medians (range) of treatment duration were 21 (18.3 - 22.1) and 16 (4.3 - 16.6) weeks in the Q2W and Q4W cohorts, respectively.The interim analysis results showed a clinically meaningful effect of emicizumab prophylaxis with the Q2W and Q4W regimens. As of the data cutoff date, 3/6 patients in the Q2W cohort and 5/7 patients including 1 patient previously untreated with FVIII in the Q4W cohort experienced no treated bleeds. There were no treated spontaneous bleeds and a total of 6 treated bleeds were traumatic. Two out of them were treated joint bleeds. Model-based annualized bleeding rates for treated bleeds with FVIII products under emicizumab prophylaxis were 1.6 (95% CI, 0.60 to 4.25) and 1.0 (95% CI, 0.25 to 4.06) in the Q2W and Q4W cohorts, respectively.All 13 patients experienced at least 1 adverse event (AE) and a total of 78 AEs were reported. There were no AEs that were grade 3 or higher, serious, led to withdrawal from treatment, or resulted in dose modification or interruption. None of the AEs were considered related to emicizumab. Neither thromboembolic events, thrombotic microangiopathy, systemic hypersensitivity reactions, nor local injection site reactions were reported. The most frequent AEs were contusion in 10 (76.9%) patients, excoriation and nasopharyngitis in 4 (30.8%) patients each, and ligament sprain and influenza in 3 (23.1%) patients each.The emicizumab exposures observed in this study were within the observed variability in preceding studies. No effects of age or body weight on emicizumab exposure were evident.Conclusions: This interim analysis results suggested clinically meaningful efficacy and favorable safety of the emicizumab Q2W and Q4W regimens in patients aged <12 years with severe hemophilia A without inhibitors. This suggests that it should be appropriate to apply the same dosing regimens of emicizumab for pediatric patients without inhibitors and other patient populations of hemophilia A. The updated results of primary analysis after completing at least 24 weeks on emicizumab treatment will be presented at the meeting. DisclosuresShima: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; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Nogami: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. Nagami:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership. Yoshida:Chugai Pharmaceutical Co., Ltd: Employment. Yoneyama:Chugai Pharmaceutical Co., Ltd: Employment, Patents & Royalties: Anti-FIXa/X bispecific antibodies . Ishiguro:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Taki:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Immunogenicity of Emicizumab in People with Hemophilia A (PwHA): Results from the HAVEN 1-4 Studies

IntroductionEmicizumab is a bispecific humanized monoclonal antibody given subcutaneously, which bridges FIXa and FX to restore the function of missing FVIIIa in PwHA. It is approved for routine prophylaxis in PwHA with inhibitors of all ages, and its efficacy and safety in PwHA without inhibitors was recently described (Mahlangu et al. N Engl J Med 2018, in press; Pipe et al. WFH 2018). Anti-drug antibody (ADA) formation is commonly observed with biologics (e.g. monoclonal antibodies). Presence of ADAs may alter the pharmacokinetics (PK) and pharmacodynamics (PD), and can affect efficacy and safety. Therefore, characterization of the rate and clinical significance of anti-emicizumab antibodies is of importance. Four patients (4/18) tested positive for ADAs in the phase I/II study of emicizumab (Shima et al. Blood Adv 2017). We optimized the immunoassay sensitivity and report here the updated analysis of the immunogenicity of emicizumab in four phase III studies: HAVEN 1, 2, 3 and 4.MethodsAll PwHA enrolled in HAVEN 1 (NCT02622321), HAVEN 2 (NCT02795767), HAVEN 3 (NCT02847637) or HAVEN 4 (NCT03020160) who had at least one ADA measurement after exposure to emicizumab were included in the analysis. Blood samples for detection of anti-emicizumab antibodies were collected at baseline and at regular intervals (initially monthly and later every 12 weeks) during emicizumab treatment or 24 weeks after the last dose for discontinuations. Samples were screened for the presence of ADAs with a sandwich enzyme-linked immunosorbent assay (ELISA) method. Positive samples underwent confirmatory analysis in the presence of unlabeled emicizumab to ensure binding specificity. The assay cut-point for ADA positivity was generated from all study patients' samples before emicizumab exposure (n=398). The confirmatory cut-point was generated from randomly selected baseline samples from these patients (n=100). ADA positivity was assessed according to the recommendations of the American Association of Pharmaceutical Scientists Therapeutic Protein Immunogenicity Focus Group (Shankar at al. AAPS J 2014). In absence of a sensitive neutralizing antibody assay, ADAs associated with consistent decline of emicizumab exposure were considered as having a neutralizing potential; associated loss of PD effect (e.g. decreased FVIII activity, decreased generation of thrombin and prolonged activated partial thromboplastin time) was reviewed as supportive information. The association between ADAs and clinical response or adverse events was also examined.ResultsOf 398 HAVEN patients included in this analysis, 14 (3.5%) tested positive for ADA (2/111, 4/88, 6/151 and 2/48 in HAVEN 1, 2, 3 and 4, respectively). For 7 patients, ADAs were transient, i.e. detected on a single occasion. Three patients (n=1 HAVEN 1; n=2 HAVEN 2), who tested positive for ADA and displayed decline of PK and reduced PD effect, were classified as having ADAs with neutralizing potential, i.e. 0.75% of the overall population. Of those, 1 patient discontinued emicizumab due to a loss of efficacy and resumed pre-study treatment without complication. The presence of ADAs without neutralizing potential was not associated with decreased efficacy. No cases of anaphylaxis or hypersensitivity were reported in ADA-positive patients. Patients who tested positive for ADA did not have a safety profile that differed from that of the overall population. Specifically, there was no trend towards increased frequency or severity of injection site reactions after patients tested positive for ADAs.ConclusionsEmicizumab treatment is associated with a low rate of patients who tested positive for ADA (3.5%), similar to other humanized monoclonal antibodies. ADAs with a neutralizing potential were observed in <1% of patients. Importantly, the presence of ADAs was not associated with impact on safety. Based on this analysis, the rate of ADA with risk of clinical consequences in patients treated with emicizumab is very low, suggesting that routine monitoring is not warranted. DisclosuresPaz-Priel:Genentech Inc: Employment. Chang:Genentech: Employment, Equity Ownership. Asikanius:Roche: Employment, Equity Ownership. Chebon:F. Hoffmann-La Roche: Employment. Emrich:Roche: Employment, Patents & Royalties. Fernandez:Roche: Employment. Kuebler:Genentech: Employment; Roche: Equity Ownership. Schmitt:F. Hoffmann-La Roche: Employment, Equity Ownership.

Management of Persons with Hemophilia A with Inhibitors After Emicizumab Approval

Introduction: Emicizumab, a bispecific antibody to factors IXa/X, was approved by the Food and Drug Administration in 2017 for prophylactic treatment of persons with hemophilia A (PwHA) with inhibitors. Compared with other treatments for PwHA, emicizumab has a novel mechanism of action. It is the first hemophilia A (HA) treatment administered subcutaneously and has a much longer half-life than previous treatments; hence, disease management with emicizumab can be different. This study aimed to evaluate how physicians manage HA in patients treated with emicizumab.Methods: This qualitative analysis is the first phase of a planned mixed-methods approach study and comprised 1-hour, blinded telephone interviews with 5 hematologists in all 4 geographic regions of the US. Physicians were included if they met the following criteria: 1) MD or DO degree; 2) board-certified hematologist; 3) practice in the US; 4) ≥2 years of experience post-residency; and 5) currently treat PwHA. To evaluate experience with emicizumab, physicians were also required to have treated a minimum number of patients receiving emicizumab (5 for physicians in hemophilia treatment centers [HTCs] and 3 for physicians in non-HTCs). A total of 5 qualitative interviews were conducted in May and June 2018 to understand the physicians' perspectives on treating PwHA with emicizumab. Interview topics included general management of PwHA, inhibitor screening and testing, management of PwHA with inhibitors, and physicians' experiences treating patients with emicizumab. We report common themes that descriptively emerged from the qualitative interviews, which will inform survey development for the quantitative phase of the study.Results: Of the 5 physicians, 3 were adult hematologists and 4 physicians reported seeing patients in an HTC. All physicians reported having at least 10 years of experience in practice post-residency. Regarding management of PwHA, physicians indicated disease severity, inhibitor status and annual bleed rate as critical factors in guiding treatment decision making. Patients who develop inhibitors require more medical engagement and frequent monitoring. Physicians reported that, from their experience, emicizumab results in a reduction in bleeds, leading to fewer office visits and less monitoring in PwHA with inhibitors. In addition, physicians reported that the need for disease management, even among patients with a phenotype with more bleeding, is lower as a result of emicizumab treatment due to decreased bleed rate and a reduction in need for additional treatments. Physicians reported that emicizumab's subcutaneous, once-weekly dosing leads to improved patients' quality of life and confidence in performing activities without bleeds. Acute bleed management with emicizumab was reported to be slightly different than before, given the boxed warning around concomitant treatment with activated prothrombin complex concentrate; however, the physicians indicated that they still recommend to treat bleeds as soon as one is suspected. Physicians articulated that some questions remain, including the role of immune therapy induction (ITI), use in low-titer inhibitors, and surgical management in patients treated with emicizumab. Physicians reported that there have been no significant access challenges and none of their patients have discontinued therapy; however, long-term monitoring and safety data are needed.Conclusions: This qualitative study suggests that management of PwHA with inhibitors receiving emicizumab is evolving. The interviewed physicians reported that their patients receiving emicizumab experience fewer bleeds and have an improved quality of life. However, questions regarding the role of ITI, surgical management, and long-term safety of emicizumab remain. Future research will provide additional insights into the current management of PwHA with inhibitors treated with emicizumab among US physicians. DisclosuresPatel:Genentech Inc: Employment. Raimundo:Genentech Inc: Employment, Other: Ownership interests PLC. Stepule:MedPanel, Inc.: Employment. Whiteley:Genentech, Inc.: Employment, Other: Ownership interests none PLC. Ko:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC.

Emicizumab Prophylaxis Provides Flexible and Effective Bleed Control in Children with Hemophilia Α with Inhibitors: Results from the HAVEN 2 Study

Emicizumab Prophylaxis Provides Flexible and Effective Bleed Control in Children with Hemophilia Α with Inhibitors: Results from the HAVEN 2 Study

PSY223 - QUALITATIVE RESEARCH IN HAEMOPHILIA A: EMICIZUMAB TRANSFORMS LIFESTYLE OF PATIENTS WITH INHIBITOR

Emicizumab is a monoclonal antibody developed for treatment of patients with haemophilia A (HA). Alongside clinical development program; qualitative data have been collected from patients and healthcare professionals (HCPs). Japanese HA patients with inhibitors from the emicizumab phase 1 study answered open-ended questions about their daily life while treated with emicizumab. Translation of their written answers was analyzed. Six French HCPs who had been in contact with French patients with inhibitors treated with emicizumab as part of the HAVEN 1 and 2 phase 3 studies were interviewed by phone. Specific interview guides were used, to collect information about the impact of emicizumab treatment in patients’ daily life. Interviews were exploratory, semi-structured, and lasted 1 hour. Thematic qualitative analysis on the interview transcripts and written answers of the phase 1 study was conducted. Then, a conceptual model was developed describing the experience of patients with HA treated with emicizumab. French HCPs (n=3 physicians, 2 nurses and 1 CRA) and Japanese patients (n=11) reported “spectacular” changes in patients’ daily lifestyle while treated with emicizumab. Patients reported changes they qualified significant: decrease in bleeding frequency, severity and associated joint/muscle pain. This led to improved emotional state, increased daily activities, better autonomy, and for some patients a major change in their daily lifestyle. Patients could travel further away from home thanks to treatment’s portability, ease of use of subcutaneous injection, and low frequency of injections. HCPs reported that patients were feeling more confident in the future, were able to make plans again, and treatment was so effective and convenient to use that some patients were not feeling ill anymore. Emicizumab significantly changed the way patients handled HA, and resulted in a transformation to their lifestyle. This may also have an impact on organization in HCPs’ health unit and medical practices.

Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors

AbstractEmicizumab (ACE910), a recombinant humanized bispecific monoclonal antibody, provides factor VIII (FVIII) cofactor bridging function to restore hemostasis in people with hemophilia A. In a phase 1 trial involving 18 Japanese patients with severe hemophilia A, once-weekly subcutaneous administration of emicizumab 0.3, 1, or 3 mg/kg (cohorts 1, 2, and 3, respectively) was well tolerated and substantially reduced annualized bleeding rates (ABRs) in the presence or absence of FVIII inhibitors. The current study represents an open-label, long-term extension of the previously reported 12-week phase 1 study, in which 16 of 18 patients continued to receive emicizumab for up to 33.3 months. Long-term emicizumab treatment was well tolerated, with no thromboembolic events reported and no neutralizing antiemicizumab antibodies developing during the course of the study. Plasma concentrations of emicizumab increased in a dose-proportional manner, with activated partial thromboplastin times remaining short. In cohorts 1, 2, and 3, respectively, median ABRs remained low at 1.4, 0.2, and 0 compared with 4.4, 0, and 0 in the 12-week study. Overall, 8 patients experienced no bleeding events (6 patients with and 2 patients without FVIII inhibitors); dose up-titration resulted in further reduction in ABRs in patients with suboptimal bleeding control; and the episodic use of clotting factors to control bleeding was reduced. In conclusion, long-term emicizumab treatment demonstrated a favorable safety profile with encouraging efficacy, irrespective of the presence of FVIII inhibitors, in patients with hemophilia A. This study was registered at www.clinicaltrials.jp as #JapicCTI-132195.

Bleeding Events and Safety Outcomes in Patients with Hemophilia a with Inhibitors: A Prospective, Multicenter, Non-Interventional Study

Bleeding Events and Safety Outcomes in Patients with Hemophilia a with Inhibitors: A Prospective, Multicenter, Non-Interventional Study