Emicizumab Treatment Research Articles

Real-world experience of emicizumab prophylaxis in Korean children with severe hemophilia A without inhibitors

PurposeHemophilia A is a genetic disorder characterized by a lack of factor VIII (FVIII). Emicizumab, a recombinant humanized bispecific monoclonal antibody, mimics the function of FVIII. In this article, we present data on an initial real-world evaluation of emicizumab use in Korean children with severe hemophilia A without inhibitors.MethodsThis study was conducted from June 2020 to March 2024 at 4 centers in Korea. The participants were pediatric patients with severe hemophilia A without inhibitors who had received emicizumab treatment for over 6 months. The mean and median annualized bleeding rates (ABRs) and mean and median annual joint bleeding rates (AJBRs) were compared.ResultsEach of the 21 patients in the study received an emicizumab loading regimen of 3 mg/kg weekly for 4 weeks, followed by a modified maintenance regimen of which 2 patients (9.5%) received a 1.5 mg/kg weekly dose, 3 patients (14.3%) received a 6 mg/kg dose every 4 weeks, and the remaining 16 patients (76.2%) received a 3 mg/kg dose every 2 weeks. Before emicizumab prophylaxis initiation, the mean and median ABRs for all patients were 7.04 (SD ± 5.83) and 6.52 (range 0–21.74), respectively. After receiving emicizumab treatment, the mean and mediam ABRs decreased to 0.41 and zero, respectively. Additionally, 85.7% of the patients achieved no bleeding events within 6 months of starting the treatment.ConclusionThese first real-world data in Korea indicate that emicizumab is effective and safe for pediatric patients with severe hemophilia A without inhibitors.

Final Analysis Results from the AGEHA Study: Emicizumab Prophylaxis for Acquired Hemophilia A with or without Immunosuppressive Therapy.

Primary analysis of the phase III AGEHA study suggested a favorable benefit-risk profile for emicizumab prophylaxis in patients with acquired hemophilia A (PwAHA); however, only patients undergoing immunosuppressive therapy (IST; Cohort 1) were included. To present final analysis results of AGEHA, including data on IST-ineligible patients (Cohort 2) and on long-term prophylaxis with emicizumab. For patients in both Cohorts 1 and 2, emicizumab was administered subcutaneously at 6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8 onward. Twelve patients (Cohort 1) and two patients (Cohort 2) were enrolled. Duration of emicizumab treatment was 8 to 639 days (median: 44.5 days) in Cohort 1 and 64 and 450 days in Cohort 2. In both cohorts, no major bleeds were observed after initial emicizumab administration. Six patients started their first rehabilitation sessions during emicizumab treatment and no rehabilitation-related bleeds occurred. Twenty-three surgeries were performed under emicizumab prophylaxis and there were no bleeds related to surgeries. Although asymptomatic deep vein thrombosis was reported in one patient in the primary analysis, no other thrombotic events occurred thereafter. Two patients developed anti-emicizumab antibodies, one of whom showed accelerated emicizumab clearance. Tailored IST approaches (delayed initiation, no use, or reduced dose) were successfully executed in three patients undergoing emicizumab prophylaxis. These results suggest that emicizumab prophylaxis has a favorable benefit-risk profile in PwAHA regardless of eligibility for IST.

Measurement of recombinant porcine factor VIII in patients with congenital haemophilia A and inhibitors in the presence of emicizumab.

Recombinant porcine factor VIII (rpFVIII) is a treatment option for break-through bleeds in patients with congenital haemophilia A with inhibitors (CHAwI) on emicizumab. However, there are limited data about the measurement of rpFVIII in the presence of emicizumab. To analyse whether rpFVIII can be measured with a chromogenic assay with bovine component (bCSA) in plasma from CHAwI on emicizumab treatment. In the first part of the study, FVIII deficient plasma was spiked with rpFVIII, in the second part, commercial plasma from CHAwI was spiked with emicizumab and rpFVIII, and in the third part, plasma from CHAwI on emicizumab treatment was spiked with rpFVIII. FVIII was then measured with bCSA and a chromogenic assay with human component (hCSA). Thrombin generation (TG) and clot-waveform analysis (CWA) were also carried out. The recovery of rpFVIII measured with bCSA is approximately 80% and is further influenced by the presence of an anti-porcine inhibitor. rpFVIII assessed with hCSA was influenced by emicizumab. CWA and TG showed a weak correlation with baseline emicizumab concentration, but peak thrombin and CWA correlated well with increasing emicizumab concentrations and rpFVIII activities. This study indicates that rpFVIII can be measured in the presence of emicizumab with a bCSA. A calibration curve for the measurement of rpFVIII with bCSA should be established.

Challenges in prophylactic therapy with Emicizumab in patients with hemophilia A: Focus on monitoring tests

Abstract This study presents a transversal investigation that we performed at Fundeni hospital (Bucharest, Romania) into the therapeutic benefits and efficacy of Emicizumab, a non-factor therapy, in the context of hemophilia A. Ten patients diagnosed with hemophilia A were closely monitored using clinical and laboratory resources during Emicizumab treatment, with an average of 12.8 months. Among these patients, six exhibited anti-factor VIII inhibitors, changing the medical strategy and adding complexity to their clinical profiles. A comprehensive approach was adopted to assess the coagulation status of patients under Emicizumab therapy. The study employed several key coagulation monitoring tools, including thrombin generation time (TGT) and thrombelastography (TEG). These methodologies generated valuable results in evaluating the patients’ coagulation profiles during the treatment regimen. Additionally, traditional coagulation assays were utilized to gain a profound understanding of the overall coagulation dynamics and to evaluate the therapeutic response. During prophylaxis with Emicizumab all patients experienced a reduced number of bleeding events. Moreover, a subset of these patients underwent major surgical procedures (orthopedic joint replacements, cholecystectomy) with successful outcomes. These findings underscore the potential of Emicizumab therapy as an effective option for hemophilia A patients, including those with inhibitors. Our research provides physicians several insights, offering a potential avenue for improved patients’ care and treatment strategies that translate in enhanced quality of life for hemophilia A patients undergoing Emicizumab therapy.

Cost-effectiveness analysis of emicizumab prophylaxis in patients with haemophilia A in India.

Emicizumab is the initial subcutaneously administered bispecific antibody approved as a prophylactic treatment for patients with haemophilia A (PwHA). This study assessed the economic evaluation of emicizumab treatment for non-inhibitor severe haemophilia A (HA) patients in India. A Markov model evaluated the cost-effectiveness of emicizumab prophylaxis compared to on-demand therapy (ODT), low-dose prophylaxis (LDP; 1565IU/kg/year), intermediate-dose prophylaxis (IDP; 3915IU/kg/year) and high-dose prophylaxis (HDP; 7125IU/kg/year) for HA patients without factor VIII inhibitors. Inputs from HAVEN-1 and HAVEN-3 trials included transition probabilities of different bleeding types. Costs and benefits were discounted at a 3.5% annual rate. In the base-case analysis, emicizumab was cost-effective compared to HDP, with an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-years (QALY) of Indian rupees (INR) 27,869. Compared to IDP, ODT and LDP, emicizumab prophylaxis could be considered a cost-effective option if the paying threshold is >1 per capita gross domestic product (GDP) with ICER/QALY values of INR 264,592, INR 255,876 and INR 305,398, respectively. One-way sensitivity analysis (OWSA) highlighted emicizumab cost as the parameter with the greatest impact on ICERs. Probabilistic sensitivity analysis (PSA) indicated that emicizumab had a 94.7% and 49.4% probability of being cost-effective at willingness-to-pay (WTP) thresholds of three and two-times per capita GDP. Emicizumab prophylaxis is cost-effective compared to HDP and provides value for money compared to ODT, IDP, and LDP for severe non-inhibitor PwHA in India. Its long-term humanistic, clinical and economic benefits outweigh alternative options, making it a valuable choice in resource-constrained settings.

Overview of the Research System Cost-effectiveness of Emicizumab in Preventing Bleeding for People with Hemophilia A

Systematic review research helps provide more scientific evidence for doctors in drug use as well as policymakers for safe, rational, and effective drug use. Emicizumab was first approved by the FDA in 2017 for patients with congenital hemophilia A and was later approved for prophylaxis. However, the high cost of Emicizumab treatment makes it difficult for patients to access the drug as well as pay for this by the insurance fund. A systematic review of studies on Emicizumab in the world that meets the conditions inclusion and exclusion criteria shows that 7 out of 8 studies (accounting for 87.5%) showed results that helped reduce total costs and increase treatment effectiveness compared to the placebo or alternatives. One study (accounting for 12.5%) resulted in increased total costs and reduced effectiveness compared to the intervention substance. Of these seven studies, one study achieved cost-effectiveness, three studies did not achieve cost-effectiveness (because ICER was lower than the willingness-to-pay threshold), and three studies could not be concluded as to whether they achieved cost-effectiveness.
 Keywords: Systematic review, cost, effectiveness, Emicizumab, Hemophilia A.

Hemophilic Pseudotumor of Paranasal Sinuses in a Child with Severe Hemophilia a Receiving Emicizumab: A Case Report

Emicizumab, a bispecific humanized monoclonal antibody, bridges activated factor IX (FIX) and FX to restore the function of missing activated FVIII in individuals with hemophilia A (PwHA). Prophylaxis with subcutaneous emicizumab promotes adequate hemostasis in PwHA. Emicizumab prophylaxis in children with hemophilia A has been approved in the United States for use in PwHA ages newborn and older, with or without FVIII inhibitors. We report a 2-year-old boy with severe congenital hemophilia A who initially received prophylaxis with standard half-life factor VIII but later switched to subcutaneous emicizumab at 6 mg/kg every four weeks due to difficult IV access and parental preference. Shortly after starting emicizumab, the patient presented to the hospital with severe episodic epistaxis from the left nostril, requiring ICU admission and ENT consultation. Despite treatment, the condition did not improve, prompting the need for imaging studies. Subsequently, the patient developed ipsilateral eye proptosis and a mass protruding from the left nostril. CT and MRI imaging of the orbit revealed an expansible soft tissue mass measuring 2 x 2.5 x 4 cm occupying the right sphenoid sinus, extending to the nasal cavity. The mass had caused erosion of the clivus and the anterior cranial fossa floor, extending to the middle cranial fossa (Figures 1 & 2). He underwent endoscopic nasal debulking of the left nostril mass, and the pathological examination revealed a cystic mass with a thick capsule and intra-cystic blood clots, consistent with the characteristics of a hemophilic pseudotumor (HP). The fibrous stroma contained hemosiderin-laden macrophages with no evidence of malignancy. Emicizumab was discontinued before the operation, and the patient received several doses of recombinant FVIII to maintain hemostasis. Despite the debulking procedure, the patient continued to experience episodic epistaxis and joint bleeding. An inhibitor assay was performed at that time and showed high levels, leading to a switch to on-demand FVIII treatment for hemophilia A with an inhibitor. Managing the bleeding episodes with bypassing agents proved challenging, and the family expressed dissatisfaction. A decision was made to resume emicizumab treatment, and the patient eventually stabilized, experiencing no bleeding for nearly six months. Additionally, he regularly follows up with ENT specialty, with no further intervention or progression of the tumor. Notably, he did not receive any bypassing agents concomitantly with emicizumab. HP is characterized by encapsulated blood clots accumulating in extravascular tissues, especially the musculoskeletal system, in patients with bleeding tendencies, particularly hemophiliacs. It is a benign, expansible, soft tissue-like mass that exerts pressure on surrounding structures, mimicking a locally invasive malignancy. HP is a hematoma that grows and causes bone erosion through repeated bleeding episodes. A literature review revealed that HP is a rare hemorrhagic complication that develops in 1-2% of patients with severe hemophilia (Magallón et al. Am J Hematol. 1994). Its occurrence in patients receiving emicizumab prophylaxis is extremely rare. The first reported case involved a Japanese child with hemophilia who presented with a pseudotumor occupying the left maxillary sinus after repeated episodes of epistaxis. The mass caused a downward deviation of the ipsilateral eye and bulged into the buccal cavity. The patient received monthly prophylaxis with emicizumab at 6 mg/kg (Kawahara et al. Int J Hematol. 2022), but unlike our patient, he received bypassing agents concomitantly. Our reported case is unique because HP developed independently of bypassing agent therapies, as the patient did not receive any bypassing agents before the tumor's development. The likely explanation is related to repeated bleeding insults to the same anatomical location, leading to the cumulative development of hematoma and HPs. Another possibility could be attributed to the known adverse thrombotic effects of emicizumab treatment. Physicians treating hemophilia should remain vigilant for abnormal clinical signs, such as new masses in patients receiving emicizumab, which could indicate HP.

AKATSUKI 48-Week Interim Analysis: Emicizumab and Immune Tolerance Induction in People with Hemophilia A and Factor VIII Inhibitors

Background: Immune tolerance induction (ITI) therapy, for the eradication of factor (F)VIII inhibitors, is indicated for people with hemophilia A (PwHA) with FVIII inhibitors. There are limited data regarding the safety of emicizumab treatment in combination with ITI, particularly regarding thrombotic events (TEs). This study, conducted in Japan, aims to evaluate the safety profile of emicizumab during and immediately after ITI. Methods: AKATSUKI is a Phase IV, open-label, non-randomized, interventional, multicenter study; the methods have been previously published (Matsushita et al. BMJ Open 2022). PwHA with FVIII inhibitors received an approved dose of emicizumab and ITI therapy. Any standard half-life (SHL) FVIII concentrate could be used for ITI, with a dosing regimen of 50IU/kg, three times a week; when using an extended half-life (EHL) FVIII concentrate, 50IU/kg twice a week was permitted. Those who achieved ITI partial success received prophylaxis with emicizumab and a FVIII concentrate starting from the date of their next study visit following investigator confirmation of partial success. Any FVIII concentrate could be used for post-ITI maintenance therapy, given as 50IU/kg once a week for the first 24 weeks followed by 50IU/kg once every 2 weeks for the next 24 weeks, followed by discontinuation of the FVIII concentrate at the investigator's discretion. The primary endpoint was evaluation of adverse events (AEs), with a key focus on TEs, and abnormal laboratory values over time during and immediately after ITI. The main secondary endpoints included number of treated bleeds and the proportion of participants meeting ITI success criteria. Partial success was achieved on the same date that the participant's blood sample showed normal FVIII recovery in addition to the participant receiving a negative FVIII inhibitor titer. Normalized FVIII recovery was defined as a FVIII recovery rate of ≥66% of the predicted value on two consecutive occasions ≥2 weeks apart, and a negative FVIII inhibitor titer was defined as achieving FVIII inhibitor levels of <0.6 BU/mL on two consecutive occasions ≥2 weeks apart. Results: Twelve participants, all of whom were male (median [range] age 2.5 [1-54] years) were included in this interim analysis (evaluation period, median [range]: 437.5 days [224-749]. Data cut-off date: December 22, 2022). Prior to the study, participants had received emicizumab (n=11), ITI (n=9), or both (n=7), and the median (range) duration of ITI in combination with emicizumab was 203.0 (7-1,002) days. Three participants used a SHL FVIII product for their ITI treatment regimen, and nine participants used an EHL FVIII product. Additional baseline characteristics are presented in Table 1. Overall, 30 AEs occurred, none of which were considered emicizumab- or FVIII concentrate-related. Two participants each experienced one serious AE: one case of pneumonia, initially caused by transmission of a viral infection, and one wound hemorrhage, which was recorded as accidental; both recovered. No participants experienced a TE. Three participants reported a total of 10 treated bleeds, all of which were categorized as traumatic and were treated with recombinant activated FVII. At data cut-off, one participant had achieved partial ITI success, having reached a negative inhibitor titer at Week 5 and normalized FVIII recovery by Week 17. This participant was then treated with emicizumab and FVIII concentrate (50IU/kg once a week). No bleeds or AEs were reported for this participant during the observational period. The changes in FVIII inhibitor titer across the study for all participants are presented in Figure 1. Conclusions: At this 48-week interim analysis, no new safety concerns or TEs were reported in PwHA receiving emicizumab and ITI. This study continues to evaluate the safety of emicizumab in conjunction with, and following, ITI therapy in PwHA with FVIII inhibitors.

Emicizumab Prophylaxis for the Treatment of Chinese Hemophilia A Patients in the Real World: A Multi-Center Retrospective Analysis

Background The real-world experiences of Hemophilia A (HA) patients receiving emicizumab prophylaxis in China are insufficient due to the high cost and later approval of emicizumab. In this study, we retrospectively analyzed Chinese HA patients with or without factor VIII (FVIII) inhibitors receiving emicizumab prophylaxis with the aim to investigate the efficacy and safety of emicizumab as well as the current status and effect of different doses of emicizumab in a real-world setting. Methods HA patients with or without FVIII inhibitors receiving emicizumab prophylaxis between June 2019 and June 2023 in China were included in the study. Data of HA patients including children and adults were retrospectively gathered from 27 hospitals all over the country. For each patient, the anonymized data were collected and telephone follow-ups were conducted to make sure the intact information collected as much as possible. Low dose and higher dose of emicizumab were defined as monthly dose <3 mg/kg and monthly dose ≥3 mg/kg, respectively. All analyses were performed using SPSS software version 25.0 (IBM Corporation, Armonk, New York, USA). Intraindividual comparisons were performed by nonparametric paired tests. Results A total of 127 male patients (10.2% [n=13] ≥18 years old; 89.8% [n=114] <18 years old) were enrolled in our study (severe: moderate = 103:24). Of these, 42 (33.1%) had FVIII inhibitors at initiating emicizumab. The median (interquartile range [IQR]) duration of emicizumab treatment was 16.0 (9.0-30.0) months. The median (IQR) annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) after emicizumab were 0.5 (0-1.5) and 0 (0-0), respectively (calculated in patients treated with emicizumab >6 months). Among the 127 patients, 67 (52.8%) patients had no bleeds at all. No intracranial hemorrhage occurred after emicizumab. Adverse events were reported in 12 (9.4%) patients and 10 (83.3%) were injection-site reactions. There were no deaths, thromboembolic events, or thrombotic microangiopathies in our study. Two (8.0%) patients had treated epistaxis after emicizumab with low dose compared with 0 (0.0%) with higher dose ( P =0.037). Four (16.0%) patients had target joints after emicizumab with low dose compared with 1 (1.0%) with higher dose ( P =0.005) (Table 1). There were no significant differences between low dose and higher dose of emicizumab prophylaxis in ABR, AJBR, the proportion of zero bleeds, the proportion of adverse events, and so on. The median (IQR) ABR was 5.0 (2.0-14.0) with prior treatment compared with 0.5 (0-1.5) with emicizumab, an 90% reduction in ABR with P value <0.001 (Table 2).Also, the use of emicizumab was also associated with significant reduction in AJBR ( P <0.001), number of target joints ( P <0.001), number of intracerebral hemorrhages ( P <0.001), inhibitor titer ( P =0.016), and days away from school/work ( P <0.001). Conclusion In this multi-center study, we indicated the efficacy and safety of emicizumab and that low dose and higher dose of emicizumab had similar efficacy in Chinese HA patients without increasing adverse events.

Real Word Data on Levels of Emicizumab and Their Correspondence with the Global Hemostatic Capacity and the Spontaneous Joint Bleeding in Patients on Emicizumab Prophylaxis

Introduction: Emicizumab has improved the management of patients with hemophilia A. However, few real-world data are available on drug plasma levels and their correspondence with global hemostatic capacity (GHC) and annualized spontaneous joint bleeding rate (ASJBR). Aims: Evaluation of the correlation between emicizumab plasma levels, GHC and ASJBR in patients on emicizumab prophylaxis. Methods: Multicenter, observational and cross-sectional study was performed in 4 Spanish hospitals. Emicizumab plasma levels and thrombin generation capacity (TGT, Genesia ®, Stago ®) of patients on emicizumab prophylaxis were determined in a central laboratory. Kinetics of clot formation was evaluated by rotational thromboelastometry (ROTEM ®, naTEM ® test, Werfen ®) in one center. Time on emicizumab prophylaxis and the number of spontaneous joint bleeds (SJB) was collected retrospectively using the clinical history. Results are expressed as median (25 th-75 th percentiles) or mean ± standard deviation depending on data distribution. A p-value < 0.05 was considered statistically significant. Results: Twenty-eight patients were included: 18 aged ≥12 years (age= 20.1 [14.7-38.9] years old) (group 1) and 10 patients aged <12 years (age= 6.1 [3.2-8.9] years old) (group 2) (p< 0.001). Globally, emicizumab levels were 46.3 ± 11.9 mcg/mL and similar between both groups: 45.2 ± 13.1 mcg/mL (group 1) and 45.9 ± 7.3 mcg/mL (group 2) (p=0.870) (Figure 1). No correlation was detected between emicizumab levels and TGT or ROTEM ®. Compared with healthy controls, patients presented lower values of thrombin generation: Peak (% compared to controls) = 41.4 (33.3-53.0) % and endogenous thrombin potential (ETP%) = 54.9 (38.9-73.4) %. However, on the contrary, ROTEM ® showed a similar procoagulant profile (example: CT and CT+CFT; p>0.05) or even higher (example: lower CFT values in patients; p= 0.023) compared to healthy subjects (Table 1). Throughout a follow-up period of 57.0 (32.3-102.3) weeks, none of the patients presented SJB (ASJBR =0). Conclusions: Emicizumab treatment provided excellent protection to patients throughout the study period. The wide interpatient variation on emicizumab plasma levels does not appear to have an impact on the development of SJB. TGT and ROTEM ® showed contradictory results: TGT describes lower thrombin generation capacity in patients compared to healthy controls, while ROTEM ® showed a similar or even higher procoagulant function in patients. Additional studies are required to explain these findings and their clinical significance.

Bone Health of Hemophilia Ａ Patients Using Emicizumab

Background: Hemophilia patients have been observed to exhibit a higher prevalence of osteoporosis compared to age-matched general population. However, the underlying mechanism responsible for this association remains poorly understood. One hypothesis proposes that factor VIII itself may possess additional physiological functions that contribute to bone health. Conversely, alternative viewpoints suggest that overall coagulation function or thrombin generation may play a pivotal role in maintaining optimal bone health. The introduction of emicizumab, a bispecific antibody that mimics the coagulation function of factor VIII but possesses a structurally distinct composition, presents an opportunity to shed light on this matter. Therefore, the primary objective of this study is to explore and compare the bone health status of hemophilia patients, distinguishing between those utilizing emicizumab and those who are emicizumab-naïve. Method: From June 2019 to June 2023, at the hemophilia center of National Taiwan University Hospital, additional examinations to assess the patients' bone health were performed with routine annual joint health evaluations for patients with hemophilia A (PwHA) and B (PwHB). This included the use of dual-energy X-ray absorptiometry scan (DEXA) to measure the bone mineral density (BMD) of the lumbar spine, hip, and femur. Furthermore, the serum levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide (CTX) were measured as reference markers for bone formation and bone resorption, respectively. The Kruskal-Wallis test was utilized to statistically evaluate the observations among the three groups. Results: The study population was divided into three distinct groups based on their hemophilia subtype and treatment: PwHA who had been utilizing emicizumab for more than one year (n=8), PwHA individuals receiving regular factor VIII treatment (n=16), and PwHB (n=10). The analysis of the collected data, as presented in the accompanying table, revealed that the three groups exhibited similar characteristics in terms of age, annual bleeding rate, and joint conditions. Moreover, no statistically significant differences were detected in the measurements of bone mineral densities (BMDs) and biomarkers. However, it is worth noting that there appeared to be a potential trend toward higher levels of P1NP in the PwHB group.In the case of PwHA patients using emicizumab, we examined the longitudinal changes in T-score of BMD over time. Notably, three PwHA patients with baseline T-scores below zero demonstrated improvements in their T-scores after one year of emicizumab treatment. Conclusion: The results of this study indicate a lack of significant disparities in bone health between individuals utilizing emicizumab and those who are not. Furthermore, our findings suggest that emicizumab usage does not lead to a decline in bone health over the observed period.

Pharmacodynamic Biomarkers in Infants with Hemophilia A Receiving Emicizumab in HAVEN 7

Background: Emicizumab, a bispecific antibody that mimics the cofactor function of activated factor (F)VIII, demonstrated a favorable safety and efficacy profile in infants with severe hemophilia A (HA) without FVIII inhibitors in HAVEN 7 (NCT04431726; Pipe et al. Blood 2022, 140[S1]: 457-459). It is known that some coagulation factors including FIX and FX, the binding targets of emicizumab, have lower plasma levels during the first 6 months of life. This research investigates whether the developing coagulation system impacts the pharmacodynamics (PD) of emicizumab prophylaxis in infants with HA enrolled to HAVEN 7 from birth to ≤ 12 months of age. Methods: Informed consent from the parents/legally authorized representative and ethics approval were obtained. PD was assessed by activated partial thromboplastin time (aPTT), FVIII activity using a chromogenic assay containing human FIX and FX (considered FVIII-like activity), and by FXIa-triggered thrombin generation (TG) assay. Plasma antigen levels of FIX and FX were determined using immunoassays. Plasma samples from 110 healthy infants (HIs; n=42, 0-3 months old; n=68, >3-24 months old) collected separately were also measured to generate age matched reference ranges. Results: In HAVEN 7, PD biomarkers, and FIX and FX plasma levels were assessed in 55 participants during the first 52 weeks of emicizumab exposure (data cut-off May 22, 2023). At baseline, mean FVIII activity was <1 IU/dL, mean TG peak height was zero, and aPTT was prolonged as expected due to the deficiency of FVIII. By the first post-baseline visit (Week 3), aPTT was normalized to the age matched reference range in most participants and was then generally maintained in the normal range throughout the treatment period. Mean (SD) FVIII-like activity increased to 22.52 (6.05) U/dL at Week 5 after the four loading doses of emicizumab and was sustained at 21-26 U/dL thereafter. Mean (SD) TG peak height increased to 67.37 (27.21) nM at Week 5 and was sustained at 67-88 nM throughout the treatment period. Mean plasma FIX and FX concentrations were not affected by emicizumab treatment. The PD biomarkers, and FIX and FX plasma levels were also analyzed as a function of age group. The loading period (first 4 weeks) was excluded and only “steady state” measurements were considered for the PD markers. All measurements were considered for FIX and FX plasma levels. Mean (SD) FVIII-like activity of 18.14 (5.40) U/dL in the youngest participants (1-2 months old) increased to 23.57 (7.64) U/dL at 3-4 months old and was similar (23-28 U/dL) in the older age groups. Age did not have a significant impact on mean TG peak height. There was no age effect on aPTT. Mean (SD) plasma FIX and FX antigen concentrations were 4.40 (1.09) µg/mL and 6.24 (1.29) µg/mL in the <1 month old participants, increased progressively with age until about 9 months old, and then stayed around 9-10 µg/mL for both FIX and FX. Lower plasma levels of FIX and FX, as well as FVIII activity were also observed in the HIs ≤3 months vs. >3 months of age. There was no significant difference in TG between ≤ 3 months vs. >3 months of age in HIs. FVIII-like activity increased with increasing emicizumab concentrations in a linear fashion up to emicizumab concentrations of 100 µg/mL. Hence, the lower FVIII-like activity in the youngest participants could be partially explained by lower mean “steady state” trough emicizumab concentrations of 48.3 µg/mL at 1 month of age, which then increased to approx. 60 µg/mL at 4-5 months of age and older. TG peak height increased with increasing emicizumab concentrations but showed large variability. Lower FIX and FX plasma levels during the first 9 months of age may also have an impact on the PD results. Even though the levels were lower in the youngest participants, increases in FVIII-like activity and TG were seen at “steady state” emicizumab in all age groups as expected based on previous studies of emicizumab. The sample sizes were small in some of the age groups analyzed. Conclusions: FVIII-like activity and thrombin generation increased, and aPTT was normalized after starting emicizumab prophylaxis in HAVEN 7. Increase with age was seen on FVIII-like activity as well as FIX and FX levels. The PD profiles of emicizumab in infants with HA were consistent with those previously observed in older children and adults with HA. Hence, even with lower levels of FIX and FX observed at the youngest participants, emicizumab showed the expected PD response.

Influence of emicizumab on protein C-mediated clotting regulation

Emicizumab, a FVIII-mimetic bispecific antibody, is insensitive to degradation by activated protein C (APC) and may thus induce a procoagulant state. We investigated the effect of emicizumab on protein C-mediated inhibition of coagulation under in vitro conditions mimicking physiological and pathological clotting activation. Thrombin generation (TG) in tissue factor-triggered hemophilic plasma containing emicizumab (50 μg/mL) was inhibited by APC or thrombomodulin in a concentration-dependent manner, and to a similar extent as in plasma added with FVIII (Kovaltry, 1 IU/mL). However, when clotting was activated via the intrinsic pathway, emicizumab-plasma displayed resistance to APC, manifested by a barely detectable prolongation of the lag time of TG, and by the lack of inhibition of FXa generation. Moreover, in contact-activated plasma added with APC, the generation of a second wave of thrombin, following prothrombin replenishment, was much greater in emicizumab-plasma than in Kovaltry-plasma, suggesting that the insensitivity of emicizumab to APC may translate in greater thrombin formation. Considering the major role played by the contact system in the thrombotic process, hemophilia A patients under emicizumab treatment might be at increased thrombotic risk.

PB0668 Emicizumab Treatment Regimen Based on Vial Size Along with Quantification of Emicizumab Plasma Concentration. Real-World Experience from a Single Pediatric Center in Argentina

PB0668 Emicizumab Treatment Regimen Based on Vial Size Along with Quantification of Emicizumab Plasma Concentration. Real-World Experience from a Single Pediatric Center in Argentina

Psychometrics and applications of a novel self-report measure of emicizumab adherence: VERITASNexGen.

Treatment adherence is critical to minimize bleeding episodes in persons with haemophilia. Suboptimal adherence increases risk of adverse medical outcomes and negatively impacts quality of life. Assessment of treatment adherence is therefore an integral component of intervention to mitigate the adverse impacts of haemophilia. To develop and validate a multifactorial, patient (self or caregiver) report adherence measure for emicizumab treatment and report the first patient-report data on adherence to specific components of emicizumab treatment (dosing, timing, injection, planning and bleeds). An IRB approved multi-site prospective study enrolled 83 participants with factor VIII deficiency being treated with emicizumab. Participants completed the 25-item VERITAS NexGen (self-report from 50 adults age 18+ years; caregiver-report from 33 parents of children aged 6months to 17years) as well as a global adherence rating (GAR) scale. Providers of participants also completed a GAR scale. Most VERITAS-NexGen subscales had good-to-excellent internal consistency reliability, test-retest reliability, and validity. VERITASNexGen scores revealed globally strong patient-reported adherence; however timing and bleed management were reported as greater challenges to adherence compared to dosing and injections. Adults struggled more with timing and planning of injections than caregivers. The VERITASNexGen is the first validated multifactorial patient-report measure of adherence designed specifically for emicizumab treatment. Results suggest excellent adherence, with only 4%-13% of participants reporting suboptimal adherence to different components of the treatment regimen. Used in conjunction with other adherence measures, VERITAS-NexGen meets a crucial need for monitoring and understanding patient adherence to emicizumab in clinical and research settings.

POSTER ABSTRACTS

POSTER ABSTRACTS

A prospective, multicenter, open-label phase III study of emicizumab prophylaxis in patients with acquired hemophilia A

BackgroundEmicizumab is a bispecific antibody that mimics the cofactor function of activated factor (F) VIII. It prevents bleeds in patients with congenital hemophilia A regardless of the inhibitor status; however, no prospective clinical studies have been conducted for emicizumab in patients with acquired hemophilia A (PwAHA). ObjectivesTo describe the primary analysis results from a prospective, multicenter, open-label phase III study evaluating the efficacy, safety, and pharmacokinetics of emicizumab in PwAHA (AGEHA; JapicCTI-205151). MethodsEmicizumab was administered subcutaneously at 6 mg/kg on day 1 and 3 mg/kg on day 2, followed by 1.5 mg/kg once weekly from day 8 onward. Predefined criteria for the completion of dosing included FVIII activity of >50 IU/dL. ResultsBy the cutoff date (April 23, 2021), 12 patients on immunosuppressive therapy were enrolled, and 11 of them (91.7%) completed emicizumab treatment. The mean trough plasma emicizumab concentration rapidly reached a steady state (1 week), achieving the efficacious level that was established in patients with congenital hemophilia A (>30 μg/mL). Before first emicizumab administration, 7 patients (58.3%) experienced 77 major bleeds. During emicizumab treatment, no major bleeds occurred in any patient. Neither death due to bleeding or infection nor any study treatment–related serious adverse event was reported. One asymptomatic, nonserious deep vein thrombosis was discovered with no laboratory findings indicating any trend toward hypercoagulation. ConclusionThese results suggest that emicizumab prophylaxis with the tested dosing regimen and completion criteria may have a favorable benefit-risk profile in PwAHA.

Cost-utility analysis of emicizumab for the treatment of severe hemophilia A patients in Canada.

EHL FVIII products and emicizumab provide clinicians with other prophylactic options for treating hemophilia A, however, it is unclear if emicizumab is a cost-saving option. The objective of this study is to estimate the health and economic effects of using prophylactic EHL FVIII, SHL FVIII, and emicizumab in severe haemophilia A patients. A state-transition Markov model evaluated the cost-effectiveness of prophylactic SHL FVIII, EHL FVIII, and emicizumab in a cohort of 2-year-old male patients over a lifetime horizon in the form of a cost-utility analysis using a Canadian provincial ministry of health payer perspective. The transition probabilities, costs, and utilities were obtained from literature and the Canadian Bleeding Disorders Registry. Probabilistic sensitivity and scenario analyses were performed to test the robustness of the model. The base-case analysis, over a lifetime horizon, resulted in a total cost and utilities per person for SHL FVIII, EHL FVIII, and emicizumab of $27.2 million (M), $36.7M, and $26.2M, respectively, and 31.30, 31.16, and 31.61 quality-adjusted life years, respectively. Emicizumab treatment resulted in 29 and 16 less bleeds in a lifetime compared to SHL FVIII and EHL FVIII, respectively. Probabilistic sensitivity analysis showed that emicizumab was cost-saving 100% of the time compared to SHL FVIII and EHL FVIII. The cost-utility analysis showed that emicizumab is more effective and may be less costly than FVIII for Canadian haemophilia A patients, conditional on drug cost assumptions. Our model indicates that emicizumab may be a potentially favourable treatment option for minimising healthcare costs and providing higher effectiveness.

Efficacy and Safety of Emicizumab Prophylaxis in Patients with Acquired Hemophilia a Who Were Deemed Ineligible for Immunosuppressive Therapy: Additional Data from the Ageha Study

INTRODUCTION: Acquired hemophilia A (AHA) is a potentially fatal hemorrhagic disease caused by the appearance of autoantibodies against factor VIII (FVIII). Immunosuppressive therapy (IST) is started immediately after diagnosis to eradicate FVIII inhibitors. This leads to remission in most patients, but infections often occur as side effects, leading to death in many cases. Emicizumab is a bispecific antibody that mimics the cofactor function of activated FVIII and prevents bleeds in patients with congenital hemophilia A regardless of inhibitor status. Emicizumab prophylaxis is expected to reduce the risk of severe bleeds in patients with AHA (PwAHA), and also allow at-risk patients to consider reducing or postponing IST, which would minimize its side effects. To investigate the safety and efficacy of emicizumab in PwAHA, we are conducting an ongoing, prospective, multicenter, open-label, non-randomized, phase III study (AGEHA; JapicCTI-205151). Primary analysis results of AGEHA suggest that emicizumab prophylaxis with a new loading regimen and completion criteria has a favorable benefit-risk profile in PwAHA. However, all enrolled patients in that primary analysis (cutoff date: April 23, 2021) had received IST before starting emicizumab, and the influence of IST, especially on efficacy data, cannot be completely ruled out. Here, we present efficacy and safety data of emicizumab in PwAHA deemed ineligible for IST at enrollment, which were collected after cutoff date of the primary analysis. METHODS: AGEHA consisted of 2 cohorts: patients already undergoing or scheduled to immediately undergo IST at enrollment (Cohort 1), and patients deemed ineligible for IST at enrollment (Cohort 2). Emicizumab was administered subcutaneously at 6 mg/kg on Day 1 and 3 mg/kg on Day 2 followed by 1.5 mg/kg once weekly from Day 8. Predefined dosing completion criteria included FVIII activity >50 IU/dL. No restriction was set on IST use during the study. AGEHA was conducted in accordance with relevant ethical standards. Data from the 12 patients enrolled in Cohort 1 (Patients 1 to 12) is beyond the scope of this presentation. RESULTS: By the cutoff date for the presentation (September 10, 2021), 2 patients had been enrolled in Cohort 2, and 1 patient (Patient 13) had completed emicizumab treatment. Durations of emicizumab treatment were 7.1 weeks in Patient 13 and 16.3 weeks in Patient 14. Clinical courses of the 2 patients are shown in Figure 1. Patient 13 was an 82-year-old female who was diagnosed with AHA 6 days before enrollment. She was judged ineligible for IST because of her poor performance status and diabetes. After starting emicizumab, the bleeding symptoms immediately disappeared and her general condition dramatically improved. Following treatment with intensive insulin therapy for diabetes, the investigator judged that IST was applicable to her. IST with prednisolone and cyclophosphamide was started on Day 5 and Day 27, respectively, and then FVIII inhibitor titer decreased and FVIII activity gradually improved. Criteria for completion of emicizumab were met on Day 64. Patient 14 was a 59-year-old female with AHA of long disease duration (1009 days) who had been receiving a prophylactic regimen of activated prothrombin complex concentrate before enrollment. She was judged ineligible for IST because IST had not been effective for a long time in the past, and because IST was nearly contraindicated due to a complication of infections associated with osteonecrosis of the jaw. During the pre-treatment period, the 2 patients experienced a total of 3 treated bleeds, 1 of which was a treated major bleed in Patient 13. During the on-treatment period, no treated bleeds and no major bleeds occurred in either patient. The requirement for coagulation factor products or transfusions decreased between the pre- and on-treatment periods. Both patients experienced adverse events (AEs), all 9 of which were grade 1 or 2. One AE (rash) in Patient 13 was considered related to emicizumab, but no modification or discontinuation of emicizumab was required. No thrombotic events, serious AEs, AEs leading to study discontinuation, or anti-drug antibodies were reported. CONCLUSIONS: These results suggest that emicizumab prophylaxis with the new dosing regimen and completion criteria is safe and efficacious for PwAHA ineligible for IST. Further, efficacy under the non-influence of IST was also suggested. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Emicizumab Switch: Real-World Data of 251 Pediatric Patients from the Pednet Registry

Background: Despite the rapid uptake of emicizumab in the pediatric hemophilia A (HA) population, real-world data on emicizumab safety and efficacy outcomes are limited to the HAVEN-2 trial (N = 85) and single center cohort studies. Aim: To report on bleeding and safety in children and adolescents with HA receiving emicizumab prophylaxis in a large prospective multicenter cohort study. Methods: Data were extracted from the ongoing PedNet Registry (Clin.gov.trial-NCT02979119; date of extraction: Jan 2022). Patients were included if they had a diagnosis of congenital hemophilia A with a baseline factor FVIII up to 25% and were < 18 years old at start of emicizumab. Patients were required to have maintenance therapy of emicizumab and bleeding data available for a minimum of 4 weeks. Patients with concomitant coagulopathies were excluded (N = 2). Bleeding data were compared during emicizumab to bleeding data before emicizumab up to a maximum of two years prior to the start of emicizumab. Patient characteristics were summarized as numbers (%) and median with IQR (P25-P75). Mean annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were estimated and compared between prophylactic regimens by negative binomial regression modelling. Results: 251 patients were included from 30 hemophilia treatment centers, see Table 1 for patient characteristics. The median age at start of emicizumab therapy was 6.1 years (IQR: 2.1 - 12.0). Median follow-up time before emicizumab was 1.51 years and during emicizumab was 1.23 years with a total of 361 patient years reported on emicizumab therapy. Most patients (94%) had severe HA and 76% of the patients were younger than 12 years at start of emicizumab therapy. Approximately one third (37%) of the patients had an inhibitor at start of emicizumab with a median peak titer of 128 BU/ml (IQR: 34 - 600). The ABR and AJBR significantly improved during emicizumab therapy in patients with and without inhibitors, see Figure 1. In patients without inhibitors the mean ABR reduced from 2.8 prior to emicizumab to 1.1 during emicizumab (p < 0.001), while the AJBR reduced from 0.8 to 0.3 (p < 0.001). Similar results were seen in patients with inhibitors. The mean ABR reduced from 5.5 to 1.1 (p<0.001), while the AJBR reduced from 2.3 to 0.3 (p<0.001). In this cohort, two serious adverse events and six adverse events were reported during emicizumab therapy in eight patients (3% of total cohort). Serious adverse events included one death unrelated to emicizumab therapy (retroperitoneal bleed in a baby treated with LMWH for CVL thrombosis) and one patient developed anti-drug antibodies without breakthrough bleeding, who continued emicizumab therapy. Non serious adverse events were all related to local injection site reaction in six patients. No TMA or thrombotic events were observed. Conclusions: This large cohort study with prospectively collected data showed improved bleeding control compared to previous therapy and a favorable safety profile during emicizumab treatment in pediatric patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal