Patients With Hemophilia A Research Articles

Additional Factor X Enhances Emicizumab-Driven Coagulation Function in Patients with Hemophilia A and Hemophilia A Mice.

Bypassing agents are used for breakthrough bleedings in patients with hemophilia A with inhibitor (PwHAwI) receiving emicizumab prophylaxis. Previous study demonstrated a weak binding affinity between emicizumab and factor (F)X (K d; 1.85 μM), and that this value was much greater than the plasma FX concentration (∼130 nM). We speculated that increased FX levels could enhance coagulation potential in emicizumab-treated patients with hemophilia A (PwHA). To investigate the relationship between FX concentrations and emicizumab-driven coagulation. Plasma FX (up to 1,040 nM) and emicizumab (50 µg/mL) were added to FVIII-deficient plasmas, and plasma-derived FX (520 nM) or recombinant (r)FVIIa (2.2 µg/mL) was added to plasmas from three emicizumab-treated PwHAwI. The adjusted maximum coagulation velocity (Ad|min1|) by clot waveform analysis and peak thrombin (PeakTh) by thrombin generation assay in them were evaluated. Emicizumab (3.0 mg/kg), human (h)FIX (100 IU/kg), and various doses of hFX (100-500 IU/kg) were intravenously administered to HA mice. Clotting time/clot formation time (CT/CFT) were assessed using rotational thromboelastometry, and blood loss was estimated by a tail-clip assay. The addition of FX to FVIII-deficient plasma with emicizumab increased Ad|min1| and PeakTh. The coagulation parameters in emicizumab-treated PwHAwI spiked with additional FX remained within the normal range as well as the additional rFVIIa. In animal models, hFX injection shortened the CT and CT + CFT. The shorter CT and CT + CFT, and the lower blood loss were evident after 200 or 500 IU/kg hFX administration, and those indices were comparable to those in wild-type mice. Supplementation with FX may improve emicizumab-driven hemostasis in PwHA.

Activated protein C resistance in the copresence of emicizumab and activated prothrombin complex concentrates

BackgroundVenous thromboembolic events have been reported in persons with hemophilia A who received emicizumab and activated prothrombin complex concentrate (APCC) concomitantly, but the relevant mechanism(s) remains unclear. We speculated that activated protein C (APC) and antithrombin (AT) resistance might be associated with these adverse events. ObjectivesTo investigate APC and AT resistance in factor (F)VIII–deficient (FVIIIdef) plasma in the presence of emicizumab and APCC. MethodsIn pooled normal plasma or FVIIIdef plasma samples mixed with emicizumab (50 μg/mL) and FVIII-bypassing agents, including recombinant FVIIa (2.2 μg/mL), APCC (1.3 IU/mL), or plasma-derived FVIIa/FX (1.5 μg/mL), the suppression effect of AT (0-2.4 μM) and APC (0-16 nM) was assessed by tissue factor–triggered thrombin generation assay. The APC effects in FVIIIdef plasma with the copresence of emicizumab, FII (1.3 μM), and/or FIXa (280 pM) were also examined. ResultsThe AT resistance in emicizumab and each bypassing agent was not observed. Moreover, APC dose-dependent suppression effect was observed in pooled normal plasma or FVIIIdef plasma mixed with emicizumab and recombinant FVIIa or plasma-derived FVIIa/FX. However, APC-catalyzed inactivation had little effect on thrombin generation assay potential in FVIIIdef plasma spiked with emicizumab and APCC. The addition of FIXa to emicizumab in FVIIIdef plasma could lead to partial APC resistance. Furthermore, FVIIIdef plasma spiked with emicizumab, FIXa, and FII was markedly resistant to APC-mediated inactivation. ConclusionFII and FIXa in APCCs were key clotting factors for APC resistance in FVIIIdef plasma supplemented with emicizumab and APCCs. The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events.

Reduced plasma factor X is associated with a lack of response to recombinant activated factor VII in patients with hemophilia A and inhibitor, but does not impair emicizumab-driven hemostasis in vitro

BackgroundThe hemostatic effect of recombinant (r) factor (F)VIIa after repetitive intermittent administration may be attenuated in patients with hemophilia A (PwHA) with inhibitors (PwHAwI) creating a clinically unresponsive status, although mechanism(s) remain to be clarified. In patients receiving prophylaxis treatment with emicizumab, concomitant rFVIIa is sometimes utilized in multiple doses for surgical procedures or breakthrough bleeding. Aim and methodsWe identified ‘unresponsiveness’ to rFVIIa, based on global coagulation function monitored using rotational thromboelastometry (ROTEM) in 11 PwHAwI and 5 patients with acquired HA, and investigated possible mechanisms focusing on the association between plasma FX levels and rFVIIa-mediated interactions. ResultsOur data demonstrated that FX antigen levels were lower in the rFVIIa-unresponsive group than in the rFVIIa-responsive group (0.46 ± 0.14 IU/mL vs. 0.87 ± 0.15 IU/mL, p < 0.01). This relationship was further examined by thrombin generation assays using a FX-deficient PwHAwI plasma model. The addition of FX with rFVIIa was associated with increased peak thrombin (PeakTh) generation. At low levels of FX (<0.5 IU/mL), rFVIIa failed to increase PeakTh to the normal range, consistent with clinical rFVIIa-unresponsiveness. In the presence of emicizumab (50 μg/mL), PeakTh was increased maximally to 80 % of normal, even at low levels of FX (0.28 IU/mL). ConclusionsUnresponsiveness to rFVIIa was associated with reduced levels of FX in PwHAwI. Emicizumab exhibited in vitro coagulation potential in the presence of FX at concentrations that appeared to limit the clinical response to rFVIIa therapy.

Emicizumab-mediated hemostatic function assessed by thrombin generation assay in an in vitro model of factor VIII-depleted thrombophilia plasma.

Patients with hemophilia A (PwHA) may have concurrent deficiency of representative anticoagulant proteins, protein (P)C, PS, and antithrombin (AT), which reduces bleeding frequency. However, emicizumab-driven hemostasis in PwHA with such thrombophilic potential remains unclarified. This study investigated the influence of natural anticoagulants on emicizumab-driven coagulation in HA model plasma. Various concentrations of PS and AT were added to PS-deficient plasma and AT-deficient plasma in the presence of anti-FVIII antibody (FVIIIAb; 10BU/mL). PC-deficient plasma was mixed with normal plasma at various concentrations in the presence of FVIIIAb. Emicizumab (50µg/mL) was added to these thrombophilic HA model plasmas, prior to tissue factor/ellagic acid-triggered thrombin generation assays. Co-presence of emicizumab increased peak thrombin values (PeakTh) dependent on PS, AT, and PC concentrations. Maximum coagulation potentials in the PS-reduced HA model plasmas remained normal in the presence of emicizumab. PeakTh were close to normal in the presence of 50%AT irrespective of emicizumab, but were higher than normal in the presence of 25%AT. Addition of recombinant FVIIa (corresponding to an administered dose of 90μg/kg) enhanced coagulation potential to normal levels. Our findings provide novel information on hemostatic regulation in emicizumab-treated PwHA with a possible thrombophilic disposition.

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.

Native American Ancestry Is Associated with Successful Immune Tolerance Induction in Admixed Brazilians with Hemophilia a

Immune tolerance induction (ITI) is the treatment of choice for eradicating neutralizing antibodies (inhibitors) against factor VIII (FVIII) in patients with hemophilia A (PwHA). Previous studies have investigated the association of ethnicity with inhibitor development with conflicting results. However, to our concern, studies targeting the role of ethnicity on ITI outcomes are still missing. Since unfavorable ITI response occurs in 30%-40% of these patients, establishing predictors of ITI response is needed. To evaluate genetic determinants of ITI outcome beyond FVIII genotype, we investigated the association of genomic ancestry and ITI response by analyzing the exomes of PwHA from the Brazilian Immune Tolerance Study (Camelo et al. 2021). PwHA were enrolled in 15 hemophilia treatment centers from all Brazilian regions. We collected clinical data and blood samples for DNA extraction. ITI was carried out using a single protocol, regardless of selection based on “good” or “bad” risk of ITI outcome. Inclusion criteria comprised patients with severe and moderately-severe (FVIII&amp;lt;2%) HA with high-responding inhibitors who completed a first course of ITI. Since the characteristics of PwHA who responded with partial and complete success yielded similar results, these groups were analyzed together. Exomes were obtained with high quality using the xGen Exome Research Panel v2 (Illumina). Quality control filters evaluated average coverage and deep coverage, phred score, genomic position, sex, heterozygosity, and duplicated SNPs. In a multiple regression analysis, we used geographic location, inhibitor levels, presence or absence of null mutations (i.e., frameshift, deletions, nonsense, and inversions; Oldenburg et al., 2002), and kinship coefficients as explanatory variables. Inhibitor levels were evaluated as historical inhibitor peak, titer immediately before the start of ITI, and inhibitor peak during ITI. We included 150 PwHA, of whom 136 (91%) had severe (FVIII&amp;lt;1%) HA, median age 0.9 years [IQR, 0.5,1.4] at diagnosis of HA. A total of 44 (29%) PwHA had ITI failure, 60 (40%) had partial success, and 46 (31%) had complete ITI success. Functional annotation showed that most SNPs were intronic (48%) and exonic (29%). We identified 808,706 variants, of which 90,075 were not reported in the dbSNP. Average ancestries of European, African, and Native American were 79.4% [IQR:75.4,83.4], 17.3% [IQR:17.0,17.6), and 3.3% [IQR:2.6,4.0], respectively (Table 1). There was an association between a higher Native American ancestry in patients with successful ITI (2% [IQR:1.95,2.05] ancestry mean) when compared with patients who failed ITI (1% [IQR:0.97,1.03] ancestry mean). A 1% increase in the Native American ancestry proportion was associated with a rise of ~10% in the probability of successful ITI ( odds ratio [OR], 10.43 [95% CI,7.45,13.41], p = 0.040 (Table 2). Neither European nor African ancestry was associated with ITI outcome. In conclusion, Native American ancestry was associated with successful ITI. To our concern, this is the first study to evaluate genomic ancestry as a predictor of ITI response and the first to enroll an admixed population of HA. Identifying ancestry as a predictor of ITI outcome may elicit different therapeutic approaches for inhibitor eradication. However, our findings may not apply to other populations due to a particular characteristic of admixture of the Brazilian population. REFERENCES Camelo, R.M. et al. (2021) ‘Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BRAZIT) study protocol’, PLOS ONE, 16(8). doi:10.1371/journal.pone.0256265. Oldenburg, J., El-Maarri, O. and Schwaab, R. (2002) ‘Inhibitor development in correlation to factor VIII genotypes’, Haemophilia, 8(s2), pp. 23-29. doi:10.1046/j.1351-8216.2001.00134.x.

Longitudinal dynamic changes in factor VIII inhibitor titers in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis.

Emicizumab prophylaxis dramatically reduces bleeding events in patients with hemophilia A (PwHA) with or without factor VIII (FVIII) inhibitors. However, long-term dynamic changes in FVIII inhibitor titers during emicizumab prophylaxis remain to be investigated. We conducted a retrospective follow-up study of FVIII inhibitor titers after initiation of emicizumab prophylaxis in 25 PwHA carrying current or historical FVIII inhibitors. Nineteen PwHA had FVIII inhibitors at initiation of emicizumab prophylaxis (age: median 22 [range 4-60] years and inhibitor titer: 30 [1.0-1450] BU/mL). In 17 of the 19 patients, the inhibitor titers markedly decreased to a median of 1.2 (< 0.6-58)BU/mL at a median follow-up of 71 (38-111) months. In two patients, titers were slightly elevated after initiation of emicizumab but decreased in the long term. The remaining six patients had negative inhibitor status (< 0.6BU/mL) when switched to emicizumab from FVIII prophylaxis. Five patients maintained negative titers. One patient had inhibitor recurrence, with a peak titer of 1.6BU/mL that decreased to 0.9BU/mL. In most cases, FVIII inhibitor titers can be expected to decrease spontaneously during emicizumab prophylaxis, but regular follow-up is necessary to manage breakthrough bleeds.

The in vitro effect of anticoagulant agents on coagulation and fibrinolysis in the presence of emicizumab in the plasmas from patients with haemophilia A.

Emicizumab is used as hemostatic prophylaxis for patients with hemophilia A (PwHA), irrespective of the presence of inhibitors. Although bacterial infection can lead to a procoagulant state, there is limited information on coagulation and fibrinolysis potentials in emicizumab-treated PwHA and on the use of anticoagulants in such cases. We examined whether anticoagulants affect the coagulation and fibrinolysis potentials in plasma from PwHA spiked with emicizumab. Plasma from PwHA was in vitro supplemented with emicizumab (50μg/mL; emi-plasma) and anticoagulants (recombinant thrombomodulin (rTM), nafamostat mesylate (NM), unfractionated heparin (UFH), or low-molecular-weight heparin (LMH)). PwHA plasma spiked with rFVIII (1 IU/mL) was used as a reference (ref-plasma). The coagulation and fibrinolysis potentials in plasma was measured by thrombin and plasmin generation assay (T/P-GA) and clot-fibrinolysis waveform analysis (CFWA). In T/P-GA and CFWA, coagulation potentials (maximum coagulation velocity; |min1|, and peak thrombin; Th-Peak) in plasma rose with increasing concentrations of emicizumab and rFVIII, but fibrinolytic potentials (peak plasmin; Plm-Peak, and maximum fibrinolytic velocity; |FL-min1|) remained unchanged. Adding rTM, NM, and UFH to emi-plasma suppressed coagulation and fibrinolysis potentials, similar to ref-plasma. Regarding the heparin, UFH and LMH inhibited the improved coagulation in emi-plasma. UFH inhibited fibrinolysis as well, but LMH did not. Anticoagulants could exhibit the inhibitory effects on the coagulation and fibrinolysis potentials in plasma from PwHA spiked with emicizumab, similar to those in normal plasma.

Coagulant potentials of emicizumab in the plasmas from infant and toddler patients with hemophilia A.

Emicizumab significantly reduces bleedings in patients with hemophilia A (PwHA). A clinical study (HAVEN 7; NCT04431726) for PwHA aged less than or equal to 12months is ongoing, but emicizumab-driven coagulation potential in PwHA in early childhood remains to be clarified. To investigate the in vitro or in vivo coagulation potential of emicizumab in plasmas obtained from infant and toddler PwHA. Twenty-seven plasma samples from 14 infant/toddler PwHA (aged 0-42months, median 19months) who received emicizumab (n=9), factor (F)VIII products (n=8), or no treatment (n=10) were obtained. FVIII activity in FVIII-treated plasmas was cancelled by the addition of anti-FVIII monoclonal antibody (mAb). Emicizumab-treated plasmas (in vivo) and emicizumab-spiked plasmas (in vitro) were analyzed. Emicizumab-untreated plasma or emicizumab-treated plasma supplemented with two anti-emicizumab mAbs were used as references. Adjusted maximum coagulation velocity (Ad|min1|) by clot waveform analysis and peak thrombin (Peak-Th) by thrombin generation assay was assessed. Ad|min1| values in 24 samples were improved by the presence of emicizumab. Values did not improve in the three remaining samples (aged 1, 23, and 31months). Although the presence of emicizumab showed an age-dependent increase in Peak-Th in 20 samples, this increase was not observed in seven samples (aged 0, 1, 1, 2, 8, 19, and 36months). Emicizumab-dependent increases in both Ad|min1| and Peak-Th were shown in 18 samples, and increases in either parameter were shown in eight samples. One sample (from patient aged 1month) showed no increase in both, however. Emicizumab could improve coagulant potential in plasmas from infant/toddler patients with hemophilia A.

Characterization of Anti-Emicizumab Antibodies Using Repository Samples Obtained in Clinical Studies of Emicizumab Conducted in Japan.

Emicizumab, a factor (F) VIII function-mimetic bispecific antibody, is used for the treatment with patients with hemophilia A (PwHA). Although the immunogenicity of emicizumab is low, potential of immunogenicity is still remained. Despite some cases of anti-drug antibodies (ADAs) reported, the characteristics of ADAs have not been fully elucidated. In this research, we evaluated the characteristics of ADAs by using repository samples collected in phase 1, phase 1/2 and bioavailability studies conducted in Japan. Ten plasma/serum samples from 6 healthy volunteers (HVs) and 4 PwHA who tested positive for ADAs in the clinical studies were used for the assessment of neutralizing activity, epitope analysis and pharmacokinetics (PK). Neutralizing activity of ADAs was observed in 3 HVs and 1 PwHA. Among these, 3 HVs developed ADAs which bound to the complement-determining region (CDR)1, 3 of the common light chain (cLC) of emicizumab and associated with shorter half-life. Epitopes of ADAs in 1 PwHA were on the Fab-regions of emicizumab, and the ADAs were not associated with decreased exposure in this PwHA. Neutralizing activity was undetectable in 3 HVs and 3 PwHA. Among these, ADAs in 2 HVs and 2 PwHA recognized the Fab-regions or the CDR 1, 3 of the cLC, and 1 of these 2 HVs showed shorter half-life of emicizumab. In conclusion, our analysis of ADAs demonstrated the various characteristics of ADAs, such as ADAs with either neutralizing activity or affected pharmacokinetics, or both properties.

Pharmacodynamics Monitoring of Emicizumab in Patients with Hemophilia A.

Emicizumab is a bispecific antibody mimicking coagulation factor VIII (FVIII) employed to treat patients with hemophilia A (PwHA) regardless of FVIII inhibitor status. The identification of biological markers reflecting the hemostatic competence of patients under emicizumab therapy would have a great clinical value. Unfortunately, emicizumab over-corrects standard coagulation assays, precluding their use for evaluating the hemostatic correction achieved in vivo. Here, we investigated whether global coagulation assays (GCA) would allow monitoring the biological response to non-factor replacement therapy with emicizumab. Six adults PwHA received a weekly dose of emicizumab of 3 mg/kg during weeks (W) 1 4 and 1.5 mg/kg from W5 onwards. Response to treatment was monitored weekly by emicizumab plasma concentration, thrombin generation (TG), and fibrin clot formation (FCF) and structure. TG and FCF results were compared to patient baseline, FVIII replacement, and healthy donors. TG and FCF significantly increased in PwHA after the loading period, reaching a plateau that lasted until the end of monitoring. Similarly, fibrin clot network became denser with thinner fibrin fibers. However, TG contrary to FCF remained at the lower limits of reference values. Remarkably, despite having similar plateau concentrations of emicizumab some patients showed markedly different degrees of TG and FCF improvement. Our study enriches the knowledge on the use of GCA to monitor non-factor replacement therapy, indicating that TG and FCF could act as direct markers of emicizumab biological activity. GCA allow to capture and visualize the individually variable response to emicizumab, leading a step forward to the personalization of patient treatment.

Impact of switching prophylaxis treatment from factor VIII to emicizumab in hemophilia A patients without inhibitors

BackgroundFactor VIII (FVIII) replacement and emicizumab are effective at preventing bleeds in patients with hemophilia A (HA). Though benefits of emicizumab among inhibitor patients with HA (PwHA) are well established, more real-world evidence among non-inhibitor patients is needed.MethodsUsing a United States healthcare claims database, we compared billed annualized bleed rates (ABRb) and the total cost of care (TCC) before and after switching from FVIII prophylaxis to emicizumab among non-inhibitor male PwHA. Bayesian inferences were used to assess the difference in ABRb and TCC per patient per year (PPPY) pre- versus post-prophylaxis switch.ResultsWe included 101 non-inhibitor male PwHA aged between 3 and 63 years old who switched from FVIII prophylaxis to emicizumab prophylaxis in 2018 or 2019. The ABRb increased from 0.52 to 0.62 (p = 0.83) after switch. The posterior probability of the mean ABRb increasing after the switch was 75.54%. The TCC PPPY increased from $517,143 to $627,005 (p < 0.0001) after switch and the posterior probability of mean costs increasing after the switch was 99.80%.ConclusionsPersonalization of care through the identification of the most appropriate therapy for each patient can optimize clinical and economic outcomes. Future real-world evidence research could help establish the value of prophylactic options in targeted populations such as the non-inhibitor male PwHA.

Mim8 Clinical Development Program: An Overview of the Frontier Studies

Background Mim8 is a bispecific antibody, mimicking activated factor VIII (FVIIIa), currently in clinical development as a treatment for patients with hemophilia A (PwHA), independent of inhibitor status. Preclinical data demonstrate that Mim8 is highly potent with an efficacious hemostatic effect. The FRONTIER program aims to expedite Mim8 development, recruiting participants from >30 countries including women, previously untreated patients (PUPs), and patients with mild/moderate disease severity. FRONTIER 1 (NCT04204408; EudraCT:2019-000465-20), a phase 1/2 study of Mim8 in healthy participants and PwHA, provided proof of concept that Mim8 enables clinically relevant levels of thrombin generation with no safety concerns, and no occurrences of anti-Mim8 antibodies. The study also used biomarker bridging (in vitro and ex vivo) to benchmark against emicizumab. The outcomes from FRONTIER 1 support the further development of Mim8 in the ongoing phase 3 studies (FRONTIER 2 and 3). Methods & Study Design To allow for rapid clinical development, the observational run-in phases of both phase 3 studies were initiated prior to FRONTIER 1 completion (Figure 1A) and are running in parallel. FRONTIER 2 (NCT05053139; EudraCT:2020-001048-24) is an ongoing, open-label, randomized control study investigating the efficacy and safety of Mim8 dosed once-weekly (QW) and once-monthly (QM) in adult and adolescent PwHA (≥12 years of age). The study aims to recruit ~250 PwHA. The primary endpoint is the annualized bleeding rate. Prior to their first Mim8 dose, patients currently on FVIII or bypassing agent prophylaxis will remain on this treatment for ≥26-week observational run-in period (Figure 1B). Patients currently treated on demand with ≥5 bleeds in the 26 weeks prior to screening can join the main phase of the trial without a run-in period. Participants receiving emicizumab must discontinue use and switch to factor prophylaxis when entering the run-in period. Exclusion criteria include planned major surgery, ongoing/planned immune tolerance induction (ITI), and previous or current thromboembolic diseases/events. FRONTIER 3 (NCT05306418; EudraCT:2020-003467-26) is an ongoing, open-label, uncontrolled study investigating the safety of Mim8 in pediatric PwHA (aged 1-11 years). It is targeting recruitment of 70 children with HA with or without inhibitors, who will receive subcutaneous doses of Mim8 QW for 26 weeks. Thereafter, participants can choose between QW and QM prophylaxis regimen for the next 26 weeks (Figure 1B). The primary endpoint is the number of treatment-emergent adverse events during the 52-week treatment period. Key inclusion criteria for FRONTIER 3 include: previously treated patients prescribed FVIII, or by-passing agents, and PUPs with severe HA. Key exclusion criteria are the same as FRONTIER 2. ITI would need to be discontinued prior to joining the trial. To collect further data on the safety and efficacy of Mim8, FRONTIER 1-3 study participants will be invited to join the long-term, open-label extension FRONTIER 4 study. Additionally, plasma samples will be collected from participants with the aim of future exploratory analysis of further biomarkers. Conclusions The FRONTIER studies are a comprehensive clinical development program designed to evaluate Mim8 in PwHA, with or without inhibitors. The FRONTIER 2 and FRONTIER 3 studies initiated recruitment prior to the completion of FRONTIER 1 to accelerate the development of a novel alternative to current HA treatments. Moreover, Mim8 is being investigated in a broad patient population across many different countries and the inclusion criteria were designed to allow for the incorporation of female patients, PUPs, all disease severities, and all ages. This aims to ensure that the study population is as comparable to and representative as possible of the real-world population of PwHA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Intracranial Hemorrhage in US Patients with Hemophilia a: Real-World Retrospective Cohort Study Using the Athndataset

Background Intracranial hemorrhage (ICH), a serious complication of hemophilia A (HA), causes high rates of mortality and morbidity (Zanon. Blood Transfus. 2019). The risk of developing ICH is 10 to 20 times higher in patients with HA (PWHA) than in individuals without (Zanon. 2019). Patient data from 1998 through 2008 identified several risk factors for ICH, including presence of an inhibitor and prior ICH (Witmer. Br J Haematol. 2010). However, standard of care and the treatment landscape have evolved (Srivastava. Haemophilia. 2020). This study leverages clinical information from the ATHNdataset to assess the incidence of ICH in non-neonate (≥2 years of age) PWHA and determine the association between ICH risk and key characteristics. Methods This retrospective cohort study used data from PWHA (male, aged >2 and <75 years) who had visit information from January 1, 2010, through September 30, 2020, as identified in the ATHNdataset. The American Thrombosis & Hemostasis Network (ATHN) is the steward of the ATHNdataset, a Health Insurance Portability and Accountability Act-compliant, de-identified patient health dataset containing data from individuals with bleeding disorders receiving care through ATHN affiliates who opt in to contribute. The unadjusted incidence rate (IR) and incidence rate ratio (IRR) were evaluated by inhibitor and prophylaxis status. Association between patient characteristics and risk of ICH (HR) was evaluated by time-to-event analysis using univariate and multivariate Cox proportional-hazards (CoxPH) models. Stratified bootstrap analysis and penalty-based ridge regression sensitivity analyses were done to account for the rarity of ICH and small sample bias. Results In over 10 years and 9 months of collected data, 135 of 7837 PWHA (1.7%) had an ICH, with a median follow-up time of 10.7 patient-years. The incidence of ICH by demographic, clinical, and treatment characteristics is described in Table 1. In the unadjusted analysis, stratification by inhibitor status had an IRR (IR+/IR-) of 1.76 (95% CI: 0.97-3.20; P=0.059). IRR (IR+/IR-) by prophylaxis status in the unadjusted analysis was 0.63 (95% CI: 0.43-0.94; P=0.02). Univariate CoxPH modeling and multivariate CoxPH modeling with interaction, with associated bootstrap and ridge regression analyses, identified factors associated with differential risk of developing ICH (Table 2). Characteristics associated with a greater risk of developing ICH include being between the ages of 2 and 12 years, having ever been on Medicaid, having had HIV, hepatitis C (HCV), or hypertension (HTN) comorbidities, and never having received factor VIII (FVIII) or prophylactic treatment. In the multivariate population analysis, the estimated HR for patients never receiving prophylaxis was 7.67 (95% CI: 0.81-3.27). This HR estimate shrunk to 2.03 (95% CI: 0.26-2.21) in the associated bootstrapping analysis and 3.09 in the associated highest penalty ridge regression analysis but was still found to be statistically significant. Inhibitor status was not found to be statistically associated with ICH. Results related to an interaction between prophylaxis and inhibitor status (Table 2) could not be interpreted because of the small sample size. Discussion ICH is a serious, life-threatening complication for PWHA, hence the need to identify factors associated with increased risk of ICH. This is the first study in a decade evaluating key demographic, clinical, and HA treatment characteristics for associated risk of PWHA developing ICH. These results demonstrate that risk factors for ICH include age (greatest risk in children between the ages of 2 and 12 years), having ever been on Medicaid, having had HIV, HCV, or HTN comorbidities, and never having received FVIII or prophylactic treatment. It was previously shown that prophylaxis confers a protective effect against ICH in instances of severe disease (Witmer 2010) and in children and adolescents (Andersson. Br J Haematol. 2017). Inhibitor positivity has been shown to increase risk for ICH (Witmer 2010; Zanon. Haemophilia. 2012); however, this study was unable to corroborate those findings. A larger sample size is required to draw substantive conclusions regarding the joint impact of prophylaxis and inhibitor status on risk of ICH. As the treatment landscape for HA evolves with the increased use of non-factor products and gene therapy, continued evaluation of risk factors for ICH will be needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A real-world study comparing pre-post billed annualized bleed rates and total cost of care among non-inhibitor patients with hemophilia A switching from FVIII prophylaxis to emicizumab

Objective Factor VIII (FVIII) replacement and emicizumab have demonstrated efficacy for prevention of bleeds among patients with hemophilia A (PwHA) compared to on-demand (OD) use. Evidence investigating clinical outcomes and healthcare costs of non-inhibitor PwHA switching from prophylaxis with FVIII concentrates to emicizumab has not been well-established within large real-world datasets. This study aimed to investigate billed annualized bleed rates (ABRb) and total cost of care (TCC) among non-inhibitor PwHA switching from FVIII-prophylaxis to emicizumab-prophylaxis. Methods This retrospective, observational study was conducted using IQVIA PharMetrics Plus, a US administrative claims database. The date of first claim for emicizumab was defined as the index date. OD patients and inhibitor patients were excluded. Bleeds were identified using a list of 535 diagnosis codes. Bayesian models were developed to estimate the probability ABRb worsens and TCC increases after switching to emicizumab. Wilcoxon rank-sum tests were used to test statistical significance of changes in ABRb and TCC after switch. Results Among the 121 identified patients, the difference in mean ABRb between FVIII-prophylaxis (0.68 [SD = 1.28]) and emicizumab (0.55 [SD = 1.48]) was insignificant (p = .142). The mean annual TCC significantly increased for patients switching from FVIII-prophylaxis ($518,151 [SD = $289,934]) to emicizumab ($652,679 [SD = $340,126]; p < .0001). The Bayesian models estimated a 21.0% probability of the ABRb worsening and a 99.9% probability of increasing TCC after switch. Conclusions This study found that in male non-inhibitor PwHA, switching from FVIII prophylaxis to emicizumab incurs substantial cost increase with no significant benefit in ABRb. This evidence may help guide providers, payers, and patients in shared decision-making conversations around best treatment options.

POSC37 Economic Cost of Treatment in Canada: A Multi-Centre, Retrospective Study

Hemophilia A (HA) is an inherited bleeding disorder, for which the standard of care (SOC) in Canada is prophylactic infusion of clotting factor (CF) VIII (FVIII). Additional on-demand infusions of FVIII or other CF may be administered to treat bleeds as needed. Up to 35% of patients with HA (PwHA) will develop inhibitors to FVIII. These patients are treated with bypassing agents, which may involve frequent and/or large doses infusions. Although HA is a rare disease, there is a substantial economic burden.

Baseline VWF:Ag Level and Body Mass Index Are Inverse Influencing Factors of Annualized Total Bleeding Rate and Annualized Joint Bleeding Rate Respectively in Severe-Type Adult Patients with Hemophilia a (PwHA) with Episodic Treatment with rFVIII

Introduction: Bleeding phenotypes of severe-type patients with hemophilia A (PwHA) vary greatly, which influence factor consumption and medical cost. Factors affecting bleeding patterns of PwHA include various procoagulant and anticoagulant factors, joint condition and physical activity, etc. We aimed to investigate clinical factors influencing by-nature bleeding frequency of severe-type PwHA during episodic treatment.Methods and materials: There were 19 non-inhibitor, severe-type, previously treated PwHA aged >20 years, who had at least one to five major joints arthropathy, retrospectively enrolled from two hemophilia centers for analysis. They had been refusing prophylaxis therapy with FVIII product due to heavy burden of frequent intravenous FVIII injection and had long-term episodic treatment. Clinical informations were collected from November 2017 to November 2018, including age, body mass index (BMI), body weight, ABO blood grouping, HCV and HIV infection status, baseline VWF:Ag and VWF:activity, mutation of F8 gene. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR), weekly doses and annualized factor consumption costs (calculated by new Taiwan dollars, NTD) were obtained from the patients' medical records.Results: The PwHA with ABR <24 had significantly lower proportion of blood-group-O patients, higher baseline VWF:Ag and VWF:activity than those with ABR >24.(P-value <0.05) The PwHA with AJBR <13 had significantly higher BMI than those with AJBR >13.(P-value <0.05) There was no significant difference in ABR, AJBR, weekly dose, and annualized factor cost between PwHA with O blood group and non-O blood group. Compared with PwHA with baseline VWF:Ag or VWF:activity <145%, those with baseline VWF:Ag or VWF:activity >145% had significantly older age (34.9 vs 53.2 years, P-value <0.05), higher BMI (25.2 vs 29.9, P-value <0.05), lower ABR (58.2 vs 12.2 per year, P-value<0.01), lower AJBR (46.8 vs 10.8 per year, P-value<0.01), lower weekly dose (42.4 vs 10.6 IU/kg/wk, P-value<0.01), and lower annualized factor consumption costs (4,177,732 vs 1,120,704 NTD, P-value<0.01). Compared with PwHA with BMI <28, those with BMI >28 had significantly lower ABR (58.2 vs 12.2 per year, P-value<0.05), lower AJBR (46.8 vs 10.8 per year, P-value<0.05), higher baseline VWF:activity (94.6% vs 190.2%, P-value <0.05), and lower weekly dose (38.5 vs 17.1 IU/kg/wk, P-value <0.05). By backward-stepwise multivariate linear regression, baseline VWF:Ag and BMI were identified as independent and significant inverse influencing factors for ABR and AJBR, respectively.(P-value <0.05)Conclusion: For severe-type adult PwHA with episodic treatment, baseline VWF:Ag or VWF:activity >145% was associated with lower ABR, AJBR, weekly dose, and annualized factor cost. BMI >28 was associated with lower ABR, AJBR, and weekly dose consumption. Baseline VWF:Ag and BMI were revealed as inverse influencing factors for ABR and AJBR, respectively. The results of our study could be useful for clinicians to have an insight into diversity of bleeding phenotypes of by-nature severe-type PwHA. For developing countries where factor concentrate resources are not enough, these clinical influencing factors might be helpful for the management of therapeutic strategies and resource allocation for severe PwHA. DisclosuresNo relevant conflicts of interest to declare.

Clinical Predictors and Prediction Models for Frequency of Total and Joint Hemorrhage in Severe-Type Patients with Hemophilia a (PwHA) with/without Intermediate-Dose Prophylaxis Therapy with rFVIII

Introduction: It was well-known that severe-type patients with hemophilia A (PwHA) had great variability in bleeding phenotypes. Factors effecting bleeding patterns of PwHA include at least treatment modality and interindividual various procoagulant and anticoagulant levels. We aimed to investigate what clinical variables could predict bleeding frequency of severe PwHA and to develop models for predicting bleeding phenotypes among severe PwHA with/without FVIII prophylaxis therapy.Methods and materials: Totally 51 severe-type previously-treated PwHA from two Hemophilia Centers in Taiwan were enrolled, who received standard half life (SHL) rFVIII products with complete consecutive bleeding records at least more than 6 months, and their medical charts 2017－2018 were retrospectively viewed. The clinical data were collected for analysis, including age, body mass index (BMI), body weight (BW), ABO blood groups, hemoglobin (Hb), hematocrit (Hct), HCV infecton, HIV infection, treatment modality, baseline VWF levels, and genetic defects. Baseline VWF activity meant the data via VWF:ACL activity or VWF:RCo. Clinical variables for annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were evaluated by multivariate linear regression (MVLR) analysis.Results: The cohort of 51 severe-type PwHA included 8 boys and 43 adults, aged 8-64. For treatment modality, there were 19 patients receiving episodic treatment (ET) and 32 receiving prophylaxis therapy (PT) with intermediate-dose standard half life (SHL) rFVIII. The mean study period was 11.9 months, range 10－14.5 months. Among them, there were 31 with HCV infection and 4 with HIV infection. PwHA with non-O blood group were 31 and those with O blood group 20. The mean baseline VWF:Ag was 115.6±55.5%, range 50%－294.7%. The mean baseline VWF:activity was 105.4±52.1%, range 41.3%－307%. ABR of ET group and PT group were 46.1±29.2 and 6.8±7.1, respectively. (p<0.0001***) AJBR of ET group and PT group were 37.3±27.7 and 6.0±6.8, respectively. (p=0.0001***) By MVLR analysis, both treatment modality and baseline VWF:Ag were recognized as inverse predictors of ABR and AJBR, and HCV infection recognized a predictor for AJBR. Age, inhibitor histroy, BMI, BW, ABO blood groups, Hct, Hb, HIV infection, and missense mutation or not were eliminated as predictors. The predictive equations by MVLR were as the following two:(1) Predictive ABR = 56.5 - 37.8 * (Treatment model) - 11.8 * baseline VWF:Ag (IU/mL).(2) Predictive e AJBR = 41.9 - 28.6 * (Treatment model) - 12.0 * baseline VWF:Ag (IU/mL) + 10.0 * (HCV infection).(1 if Treatment model is PT, 0 if Treatment model is ET. 1 if HCV infection or anti-HCV antibody is positive, 0 if HCV infection or HCV antibody is negative.) Separate prediction models developed from MVLR analysis could explain 52.51% of the ABR variability and 50.56% of the AJBR variability. The correlation between predicted and observed bleeding frequency was significantly strong.(P-rank>0.7, p-value<0.0001***) Mean difference between predicted ABRs and observed ABRs was 1.75 and that between predicted AJBRs and observed AJBRs was 1.27. Predicted ABR deviated <21 (<2 per month) of observed ABR in 42/50 patients (84%). Predicted AJBR deviated < 24 (<2 per month) ofobserved AJBR in 44/50 patients (88%).Conclusion: Prophylaxis therapy and baseline VWF:Ag levels were the strongest two inverse predictors for ABR and AJBR. Positive HCV infection was another predictor for AJBR. The prediction models provided with an insight into personal bleeding quantified patterns and may identify PwHA with high bleeding risks based on individual characteristics of treatment modality, baseline VWF:Ag, and HCV infection. Our approach is of help for individualized treatment and refining of dosing strategies. DisclosuresNo relevant conflicts of interest to declare.

Real-World Bleeding Outcomes, Weekly Factor Consumption Doses, Annualized Factor Costs in Severe-Type Patients with Hemophilia a (PwHA) before and after Switching to Extended Half-Life rFVIII-Fc Prophylaxis

Introduction: Stand half-life (SHL) rFVIII had been used in patients with hemophilia A (PwHA) for episodic treatment (ET) and prophylaxis therapy (PT) for years. Extended half-life (EHL) rFVIII had been available since 2014, also available in Taiwan since 2018, and resulted in markedly increased willingness for PT because it reduced injection burden. We aimed to investigate the real-world bleeding outcomes, weekly factor doses, and factor costs of severe-type PwHA with pre-switch SHL rFVIII and post-switch EHL rFVIIIFc prophylaxis in Taiwan, and made a pre-switch and post-switch comparison.Methods and Materials: There were totally 51 non-inhibitor, severe-type PwHA, with complete bleeding records before and after switching from SHL rFVIII to EHL rFVIII-Fc, enrolled from two hemophilia centers during Nov, 2018－July, 2019. Most of them had various degree of one to more major joints arthropathy, except children. The medical charts were retrospective reviewed and data were collected, including body features and factor regimen, etc. Patients' annualized bleeding/joint-bleeding rate (ABR/AJBR), weekly doses (WD), annualized factor costs (AFC) were obtained from the chart records of pre-switch 12 months and post-switch at least more-than 6-month until July, 2019. Data from scheduled operation or hospitalization due to trauma or accidence were excluded.Results: There were 8 boys and 43 adults, the median age of all PwHA when switching was 35.6 years (10.5-62). Before switching, these 51 PTP treated with SHL rFVIII who received ET (ET group), irregular prophylaxis (IP group), and regular prophylaxis (RP group) were 19 (37.3%), 7 (13.7%), and 25 (49%), respectively. Bleeding records of 51 PTP treated with SHL rFVIII were traced back with 11.8±0.9 months. After switching to rFVIII-Fc, 3 PwHA receiving ET were excluded, and bleeding records of 48 received RP were obtained with 14.7±4.6 months. Pre-switch and post-switch prophylaxis rate were 62.7% (32/51) and 94.1% (48/51), respectively. For comparison of pre-switch and post-switch outcomes: Median ABR was reduced from 48, 12, and 4 to 1.15, 1.9, and 1.5 for ET, IP, and RP group, respectively. Median AJBR was reduced from 32, 11, and 4 to 0.95, 0.7, and 1.2 for ET, IP, and RP group, respectively. Median WD was increased from 38.4, 52.9, and 63.6 IU/kg/wk to 84.6, 84.5, and 84.9 IU/kg/wk for ET, IP, and RP group, respectively. Median AFC was increased from 4,141,800, 4,064,000 and 5,129,700 NTD to 7,042,325, 5,835,450, and 5,762,810 NTD for ET, IP, and RP group, respectively. Comparing pre-switch and post-switch outcomes of children and adults who received pre-switch and post-switch prophylaxis, median ABR was reduced from 3 and 5 to 1.35 and 1.85 for children and adults, respectively. Median AJBR was reduced from 3 and 4 to 1.35 and 1.15 for children and adults, respectively. Median WD was increased from 58.8 and 58.3 IU/kg/wk to 87.85 and 83.85 IU/kg/wk for children and adults, respectively. Median AFC was increased from 4,104,225 and 5,879,025 NTD to 4,419,800 and 6,024,916 NTD for children and adults, respectively. For all PwHA, zero ABR accounted for 5.9% (3/51) with pre-switch SHL rFVIII treatment and for 20.8% (10/48) with post-switch rFVIII-Fc prophylaxis. Zero AJBR accounted for 9.8% (5/51) with SHL rFVIII treatment and for 33.3% (16/48) with rFVIII-Fc prophylaxis. For PwHA with pre- and post-switch prophylaxis, zero ABR accounted for 12.5% (1/8) and 8.3% (2/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 25% (6/24) respectively, for children and adults on rFVIII-Fc prophylaxis. Zero AJBR accounted for 12.5% (1/8) and 16.7% (4/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 37.5% (9/24) respectively, for children and adults on rFVIII-Fc prophylaxis.Conclusion: In real-world setting, for pre-switch ET group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >95%, and mean WD increased >50%. For pre-switch IP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >80%, and mean WD increased >35%. For pre-switch RP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR also reduced >45%, and mean WD increased >20%. The proportions in zero ABR and zero AJBR as post-switch rFVIII-Fc prophylaxis were increased. No matter in ET, IP, or RP group, after switching to RP with rFVIII-Fc, improvement for bleeding outcomes was quite evident. DisclosuresNo relevant conflicts of interest to declare.

Serum TNF-α Level as a Possible Predictor of Inhibitor Levels in Severe Hemophilia A.

Background The development of factor VIII (FVIII) inhibitor in patients with hemophilia A (PWHA) is a great challenge for hemophilia care. Both genetic and environmental factors led to complications in PWHA. The development of inhibitory antibodies is usually induced by the immune response. Tumor necrosis factor α (TNF-α), one of the cytokines, might contribute to its polymorphism. In this study, we investigated the clinical factors, level of serum TNF-α, and polymorphism of c.−308G > A TNF − α gene in inhibitor development in severe PWHA. Methods A cross-sectional study was conducted among all PWHA in West Java province. The clinical parameters, FVIII, FVIII inhibitor, and serum TNF-α level were assessed. The genotyping of −380G > A TNF-α gene polymorphism was performed using polymerase chain reaction and Sanger sequencing. Results Among the 258 PWHA, 216 (83.7%) were identified as severe PWHA. The FVIII inhibitor was identified in 90/216 (41.6%) of severe PWHA, consisting of 45 high-titer inhibitors (HTI) and 45 low-titer inhibitors (LTI). There was a significant correlation between serum TNF-α level and the development of HTI (p = 0.043). The cutoff point of serum TNF-α level, which can be used to differentiate between HTI and LTI, was 11.45 pg/mL. The frequency of FVIII replacement therapy was significant only in HTI of severe PWHA regarding serum TNF-α level (p = 0.028). There is no correlation between polymorphisms of −380G > A TNF-α gene and inhibitor development (p = 0.645). Conclusions The prevalence of FVIII inhibitor in severe PWHA in West Java, Indonesia, was 41.6%. The frequency of replacement therapy is a risk factor for inhibitor development. Serum TNF-α level might be used to differentiate between high and low inhibitor levels in severe hemophilia A, and this might support decision making regarding treatment options for inhibitor in severe hemophilia A.