Effectiveness of emicizumab in preventing bleeding events in severe and moderate hemophilia A: A single‐center experience in Bangladesh

Abstract Emicizumab is a monoclonal antibody that bridges activated factor IX (FIX) and factor X (FX) to replace the function of missing activated factor VIII (FVIII) in hemophilia A patients irrespective of FVIII inhibitor status. This study assessed the effectiveness of emicizumab in preventing bleeding episodes in patients with hemophilia A. This observational study included patients with moderate to severe hemophilia A who were undergoing episodic FVIII replacement therapy. The primary endpoint was the difference in annualized bleeding rates (ABR) and the secondary endpoint was the difference in Hemophilia Joint Health Score (HJHS) before and after emicizumab prophylaxis. A total of 30 male hemophilia patients were included, the mean age was 16.7 (SD: ±8.1) years, and most of them had moderate hemophilia A [63.3%]. Before prophylaxis, the median ABR was 48 (interquartile range [IQR]: 35–60), and 93.3% of patients had ABR greater than eight, whereas after prophylaxis the median ABR decreased significantly (median [IQR]: 0 [0.0–0.4], p < 0.001), and 56.7% had zero bleeds. ABR was not significantly different in patient with and without FVIII inhibitors. The HJHS scores significantly improved after prophylaxis (10 vs. 2.5, p < 0.001). The bleeding events were reduced significantly (23 vs. 0.0, p < 0.001), and zero new target joints were reported after prophylaxis. Most of the patients [93.3%] did not face any serious adverse events after prophylaxis. Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events among participants with hemophilia A, regardless of inhibitor status.


INTRODUCTION
Hemophilia is one of the inherited bleeding disorders with a distinct genetic, epidemiological, biochemical, and clinical profile [1].
Hemophilia is caused by a mutation in the factor VIII (FVIII) gene that causes a deficiency or dysfunction of coagulation clotting factor.A severe clinical bleeding phenotype, evident as spontaneous bleeding, becomes apparent when the FVIII level drops below 1% of the normal range in most hemophilia A patients [2].Among the prominent indicators of hemophilia A is intra-articular bleeding, especially in the knee, elbow, and ankle joints.The recurrence of bleeding within joints is the chief contributor to morbidity, gradual and irreversible joint impairment, and the occurrence of hemophilic arthropathy in patients with hemophilia A [3].
Replacement of the missing FVIII with FVIII infusion is used to treat bleeding, which can occur in the muscles, skin, and mucous membranes, as well as joints.Replacement therapy in hemophilia A is related with favorable outcomes, including enhancement of quality of life [4], reduced musculoskeletal complications [4,5], and lower morbidity and mortality [4,6].However, administering episodic FVIII replacements does not change the inherent course of spontaneous bleeding, eventually leading to musculoskeletal damage and other complications due to bleeding.Therefore, the widely accepted practice of using prophylaxis, in which a clotting factor is administered to prevent spontaneous bleeding and sustain protective FVIII plasma trough level, is being adopted for hemophilia patients [7].The primary concerns in hemophilia A replacement therapy are the development of anti-FVIII neutralizing antibodies (inhibitors) and the increased treatment workload due to intravenous administration and prevention efforts [8,9].Inhibitors arise as the most challenging complication of replacement therapy, affecting as many as 30% of hemophilia A patients and undermining the effectiveness of replacement therapy [10,11].Thus, non-factor replacement treatments for hemophilia A have been developed due to the high treatment burden and lower therapeutic efficacy of FVIII concentrate in hemophilia patients with inhibitors.
The monoclonal antibody and FVIII mimetic antibody, emicizumab, is one of the few registered non-replacement therapies used worldwide to treat hemophilia A. Emicizumab is a recombinant, humanized, monoclonal bispecific modified immunoglobulin G4 (IgG4) antibody that bridges activated factor IX and factor X to restore the function of missing activated FVIII in hemophilia A [12].Due to its half-life lasting around 30 days, emicizumab necessitates less frequent admin- anti-emicizumab antibody appearing during the course of treatment in patients with hemophilia A [17,18].Because of improved pharmacokinetic profile and subcutaneous administration, emicizumab is likely to have a direct impact in reducing treatment and disease burden in hemophilia A patients.
Although studies have been conducted to determine the safety and efficacy of emicizumab in hemophilia A patients, but this was not assessed in our country perspective.Therefore, we conducted this study in Bangladesh to evaluate the effectiveness of emicizumab in treating hemophilia A. The findings of this study will contribute to the literature on the safety and efficacy of emicizumab in treating hemophilia A, and may have implications for future research and clinical practice and provide valuable insights for clinicians and researchers particularly in light of the growing burden of bleeding disorders and the increasing demand for evidence-based interventions.

Study design and participants
This single-center, observational study was conducted in the hemophilia treatment center (HTC) of a tertiary care hospital for a period of one year.The study protocol was approved by ethical review committee of Dhaka Medical College (ERC-DMC/ECC/2021/114).A total of 60 hemophilia A patients were approached initially and among them 30 patients who fulfilled the selection criteria were selected.
The selection criteria involved patients with severe hemophilia A and moderate hemophilia A with severe bleeding phenotype with ABR of > 8 irrespective of FVIII inhibitor status.Hemophilia individuals who were receiving episodic FVIII replacement therapy, were eligible to participate.To determine the differences in the ABR and hemophilia joint health score (HJHS) in children and adults, the patients aged ≤18 years were considered as children and adolescents and more than 18 years were considered as adults [19].Participants who had suitable hematological, hepatic, and renal functions were included.
Suitable hematologic function was defined as having a platelet count ≥100,000/µL and a hemoglobin level of ≥8 g/dL (4.97 mmol/L).
Suitable hepatic function was defined as having a total bilirubin level ≤1.

Study procedure
Before administration of emicizumab prophylaxis therapy, all patients were screened for FVIII inhibitors.Among the 30 patients, eight hemophilia A patients had FVIII inhibitors and 22 had no FVIII inhibitors.The ABR was calculated from the previous 6 months of bleeding history using the formula of the number of reported bleeding events, divided by the number of months in the reporting time window, and multiplied by 12.The joint health was evaluated by HJHS, which incorporates nine parameters: swelling (0-3), duration of swelling (0-1), muscle atrophy (0-2), crepitus on motion (0-2), flexion loss (0-3), extension loss (0-3), joint pain (0-2), strength (0-4) for elbows, knees, and ankles, and a global gait score (0-4).The HJHS scores range from 0 to 20 per joint and the global gait score ranges from 0 to 4, resulting in a total HJHS score from 0 to 124 points.A higher score indicated a worse joint health [20].Emicizumab prophylaxis was administered by subcutaneous injection.Prophylactic treatment plan consisted of four initial loading doses of 3 mg/kg bodyweight per week, followed by a maintenance dose of 6 mg/kg every 4 weeks for at least 6 months in total at the study site.Individuals who had previously undergone episodic FVIII replacement therapy before joining the study were allowed to continue their usual prophylactic routine until after the second emicizumab loading dose, to prevent bleeding incidents prior to achieving sufficient emicizumab levels.Throughout the study period, patients and their caregivers were properly instructed to keep records of every breakthrough bleeding event and inform the HTC.Patients were followed up regularly and at each visit, detailed history of breakthrough bleeding was recorded regarding site, and severity of bleed, whether spontaneous or traumatic, and what management was taken for bleeding control.Significant bleeding events were managed with FVIII replacement therapy at HTC.For patients with inhibitor, breakthrough bleeding was managed with fresh frozen plasma (FFP) and tranexamic acid, a synthetic derivative of lysine used as an antifibrinolytic to treat major bleeding.Any side effect of the drug was properly evaluated.At each visit, bodyweight was taken for dose adjustment.

Study endpoints
The primary endpoint of this study was to evaluate the percentage reduction of ABR from the baseline to over a period of 6 months.In this context, a 100% reduction of ABR was considered as the elimination or cessation of bleeding events.Secondary endpoints included HJHS and additional bleeding-related endpoints: number of bleeding events, ABRs with inhibitor status, and presence of target joint bleeding before and after emicizumab prophylaxis.Target joints were defined as major joints (e.g., hip, elbow, wrist, shoulder, knee, and ankle) in which three or more bleeding events occurred over a 6-month period.We also assessed the differences in the primary and secondary endpoints in children, adolescents, and adults.

Statistical analysis
We used descriptive statistics to demonstrate the information of the participants who were enrolled.Continuous data were expressed as means and standard deviation (SD) or median and interquartile range (IQR) depending on the distribution of data.Categorical variables were expressed as frequencies and percentages.Comparisons of ABRs, number of bleeding events, and HJHS before and after prophylaxis were assessed by Mann-Whitney U test and Wilcoxon signed rank test, where p-value less than 0.05 was considered significant.

Demographic and bleeding characteristics
All 30 male hemophilia A patients received a subcutaneous loading dose of emicizumab at 3 mg/kg once weekly for the initial 4 weeks, and then 6 mg/kg once every 4 weeks as maintenance regimen.Among the hemophilia A patients, the mean age of the patients was 16.7 (SD: ±8.1) years, which ranged from 3.5 to 37 years and the median age of first bleeding event was 7.5 (IQR: 6.0-13.5)months.Most of the patient had moderate hemophilia A [63.3%].At baseline, the presence of FVIII inhibitor and target joint was 26.7% and 86.7%, respectively, and all the patients took episodic FVIII replacement therapy.The median bleeding event was 23 (IQR: 16-32), and life-threatening bleeding like intra-cranial bleeding was reported in 63.6% (Table 1).

Primary endpoint
Afteremicizumab patients had one to eight bleeds, and two [6.6%] patients had more than eight bleeds (Figure 1).
After emicizumab prophylaxis, the bleeding events were significantly reduced (p < 0.001).Among these 13 patients who had new bleeding event during emicizumab regimen, 43.3% had only joint bleeding, 15.4% had both gum bleeding and joint bleeding, 7.7% had both hematuria and joint bleeding, and 7.7% patients had muscle bleeding (Table S1) and zero new target joint bleeding was observed.The ABR decreased significantly in both patients with and without inhibitors (p < 0.001).There was no significant difference in ABR between patients with and without inhibitor after emicizumab prophylaxis (Table S2).

Efficacy of emicizumab prophylaxis on children and adult patients of hemophilia A
After prophylaxis, the median ABR and bleeding event was 0.0 [0.0-2.0] and 0.0 [0.0-2.0],respectively, in children and adolescents.There was no significant difference in the ABR and bleeding event between children and adult patients of hemophilia A after taking emicizumab.
The HJHS score did not differ significantly between adults and children TA B L E 1 Baseline demographics and disease characteristics of hemophilia A patients (n = 30).a Target joints were defined as major joints (e.g., hip, elbow, wrist, shoulder, knee, and ankle) in which at least three bleeding events occurred over a period of 24 weeks.

Before prophylaxis n (%)
After an allergic reaction and another patient had sleep disturbance and palpitation.Allergic reaction was managed by antihistamines, and sleep disturbance and palpitation were managed by counseling (Table 4).

DISCUSSION
The results from the present study suggested that emicizumab could offer satisfactory protection against bleeds and clinically significant bleeding control irrespective of FVIII inhibitor status, consistent with previous study findings [14,15,21].The ABR and HJHS of the patients were significantly reduced after prophylaxis in comparison to prior no prophylaxis.After prophylaxis, majority [50%] of patients had a 100.0%reduction of ABR.There was no significant difference between patients with or without inhibitor regarding ABR.Most of the patients did not face any adverse events.Additionally, despite majority of the participants presented with target joints at baseline, 100% of patients reported zero treated target joint bleeds after receiving emicizumab prophylaxis, which was higher than the published studies of both standard and extended half-life FVIII prophylaxis regimens [3,22,23], indicating that emicizumab prophylaxis given subcutaneously can provide effective bleed prevention.This is the first study to investigate the efficacy and safety of emicizumab prophylaxis in adults and adolescents with hemophilia A, both with and without FVIII inhibitors in Bangladesh, a lower middleincome country where only 5.5% of hemophilia A patients receive prophylactic treatment and most of the patients cannot afford standard treatment and are receiving inadequate on-demand therapy for hemophilia A [24].Majority of the participants included in the study were above the age of 18 years, had spontaneous bleeding episodes of more than 20, were mostly moderate cases of hemophilia A, and did not have FVIII inhibitors or a record of ITI therapy or prior use of bypassing agents, which was anticipated and consistent with

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times the upper limit of normal (ULN) and both AST (aspartate aminotransferase) and ALT (alanine aminotransferase) levels of less than or equal to three times the ULN at the time of screening.Suitable renal function was defined as having a serum creatinine level ≤2.5 times the ULN and a creatinine clearance of ≥30 mL/min, defined by Cockcroft-Gault formula.Patients showing any clinical signs or have known laboratory or radiographic evidence consistent with cirrhosis were excluded.Top-of-form patients were ineligible for the study if they had ongoing/planned immune tolerance induction (ITI) therapy.All participants and their legal guardians were informed details about emicizumab, study characteristics, and purpose of the study in an easily understandable way.All information regarding the benefits and hazards of the study was delivered to all the participants and their legal guardians, and only those who agreed to participate after written informed consent were included in the study.The research was conducted following the guidelines outlined in the Declaration of Helsinki and adhering to Good Clinical Practice.Information was gathered via an interview utilizing a structured questionnaire.

F I G U R E 1
Comparison of endpoints before and after emicizumab prophylaxis (n = 30).

neutralizing Novelty statement: What is the new aspect of your work?
[14][15][16][17]omology with FVIII, it is not anticipated to trigger the development of FVIII inhibitors and can function irrespective of the presence of FVIII inhibitors[13].Emicizumab has demonstrated efficacy in bleeding prevention, reducing annualized bleeding rates (ABRs)[14][15][16][17]and long term administration of emicizumab are well-tolerated with no thromboembolic episodes and no

Table 4
demonstrates that 27 [90%] patients did not face any adverse events after emicizumab prophylaxis, whereas one [3.3%]patient had Comparison of ABR, HJHS, and bleeding events in children/adolescents and adults after emicizumab prophylaxis (n = 30).