Mild Hemophilia A Research Articles

Clinical and Humanistic Burden of Non-inhibitor HaemophiliaA in Five European Countries: Insights from the CHESSII Study.

HaemophiliaA (HA) is a congenital bleeding disorder caused by a deficiency/absence of factorVIII (FVIII) and characterised by frequent, acute and prolonged spontaneous or traumatic bleeding events, often leading to haemophilic arthropathy and progressive joint deterioration. HA severity is characterized by endogenous FVIII activity: mild (> 5-40%), moderate (1-5%), or severe (< 1%). HA poses a substantial clinical and socioeconomic burden on people with HA (PWHA), their caregivers, and society. This analysis evaluates clinical and patient-centric outcomes of a cohort of individuals with non-inhibitor HA sampled from France, Germany, Italy, Spain, and the UK in the 'Cost of Haemophilia in Europe: A Socioeconomic Survey II' (CHESSII) study. CHESSII was a cross-sectional burden-of-illness study collecting clinical and socioeconomic data on adult (≥ 18years) individuals with haemophiliaA or B of any severity with or without inhibitors from eight European countries. Descriptive analyses were conducted examining physician-reported demographics, clinical and health resource utilisation information. PWHA-reported health-related quality of life (HRQoL) using the EQ-5D-5L and Work Productivity and Activity Impairment (WPAI) were also examined. Outcomes were stratified by HA severity and reported at country level. Demographics and clinical characteristics of the cohort (N = 880) were generally consistent across countries. Individuals with severe HA experienced more frequent bleeding events and joint disease despite broad use of factor replacement therapy long-term prophylaxis. A minority of those with mild or moderate HA also experienced such challenges. HRQoL and workforce participation diminished, and chronic pain increased, with increasing HA severity. This analysis provides up-to-date insights on the impact of HA across five European countries. Increasing HA severity was generally associated with worse clinical outcomes, HRQoL and workforce participation. These findings suggest a place for continued evidence-based tailored treatment and clinical management approaches in addressing the residual burden of HA.

Can German Health Insurance Claims Data Fill Information Gaps in Rare Chronic Diseases: Use Case of Haemophilia A.

Claims data are increasingly discussed to evaluate health care for rare diseases (resource consumption, outcomes and costs). Using haemophilia A (HA) as a use case, this analysis aimed to generate evidence for the aforementioned information using German Statutory Health Insurance (SHI) claims data. Claims data (2017-2019) from the German SHI 'AOK Bayern - Die Gesundheitskasse' were used. Patients with ICD-10-GM codes D66 and HA medication were included in descriptive analyses. Severity levels were categorized according to HA medication consumption. In total, 257 patients were identified: mild HA, 104 patients (mean age: 40.0 years; SD: 22.9); moderate HA, 17 patients, (51.2 years; SD: 24.5); severe HA, 128 patients, (34.2 years; SD: 18.5). There were eight patients categorized with inhibitors (37.8 years; SD: 29.6). Psychotherapy was reported among 28.8% (mild) to 32.8% (severe) of patients. Joint disease was documented for 46.2% (mild) to 61.7% (severe) of patients. Mean direct costs per patient per year were 1.34× for mild, 11× for moderate, 81× higher for severe HA patients and 223× higher for inhibitor patients than the mean annual expenditure per AOK Bayern insurant (2019). German SHI data provide comprehensive information. The patient burden in HA is significant with respect to joint disease and psychological stress regardless of the HA severity level. The cost of HA care for patients is high. Large cost ranges suggest that the individual situation of a patient must be considered when interpreting costs. The main limitation of SHI data analysis for HA was the lack of granularity of ICD codes.

The Role of Clot Waveform Analysis and Related Parameters in the Diagnosis and Treatment of Hemophilia A.

Hemophilia A (HA) is an inherited bleeding disorder caused by a deficiency or defect in factor VIII (FVIII). We investigated the role of clot waveform analysis (CWA) of activated partial thromboplastin time in the diagnosis and therapeutic monitoring of HA. The changes in CWA parameters the maximum clotting velocity (|Min1|), maximum clotting acceleration (|Min2|), and maximum clotting deceleration (|Max2|) were detected among mild, moderate, and severe HA groups. As the severity of HA subtypes increased, the levels of |Min1|, |Min2|, and |Max2| progressively decreased (p < 0.05). Receiver operating characteristic curve analysis showed that |Max2| and |Min2| were more effective than |Min1| in distinguishing different types of HA patients, with higher diagnostic efficacy. The standard curves based on Actin FSL reagent for normal and low levels of FVIII:C-|Max2| were established, with R2 values of 0.98 and 0.99, respectively. These curves can be utilized for monitoring during replacement therapies involving full-length recombinant FVIII and B-domain-deleted FVIII. Thirty cases of HA patients utilized the FVIII-|Max2| standard curve to obtain individual pharmacokinetics characteristic parameters. The clearance, half-life (t1/2), time to FVIII:C of 1% above baseline (tt1%), and predicted dosage showed no statistically significant differences compared with one-stage assay (p > 0.05). CWA is an economical and practical tool, and its related parameters are associated with the severity of HA. It has promising clinical prospects in predicting FVIII:C levels and individualized treatment when HA patients undergo replacement therapy.

Disease Burden, Clinical Outcomes, and Quality of Life in People with Hemophilia A without Inhibitors in Europe: Analyses from CHESS II/CHESS PAEDs.

Introduction Limited data relating to treatment burden, quality of life, and mental health burden of hemophilia A (HA) are currently available. Aim To provide a comprehensive overview of unmet needs in people with HA (PwHA) using data generated from the Cost of Haemophilia in Europe: a Socioeconomic Survey-II (CHESS II) and CHESS in the pediatric population (CHESS PAEDs) studies. Methods CHESS II and CHESS PAEDs are cross-sectional surveys of European males with HA or hemophilia B (HB) aged ≥18 and ≤17 years, respectively. Participants with FVIII inhibitors, mild HA, or HB were excluded from this analysis, plus those aged 18 to 19 years. Annualized bleeding rates (ABRs), target joints, and other patient-reported outcomes were evaluated. Results Overall, 468 and 691 PwHA with available data for the outcomes of interest were stratified by hemophilia severity and treatment regimen in CHESS II and CHESS PAEDs, respectively. In these studies, 173 (37.0%) and 468 (67.7%) participants received FVIII prophylaxis, respectively; no participants received the FVIII mimetic emicizumab or gene therapy. ABRs of 2.38 to 4.88 were reported across disease severity and treatment subgroups in both studies. Target joints were present in 35.7 and 16.6% of participants in CHESS II and CHESS PAEDS; 43.8 and 23.0% had problem joints. Chronic pain was reported by a large proportion of PwHA (73.9% in CHESS II; 58.8% in CHESS PAEDs). Participants also reported low EQ-5D scores (compared with people without HA), anxiety, depression, and negative impacts on their lifestyles due to HA. Conclusions These analyses suggest significant physical, social, and mental burdens of HA, irrespective of disease severity. Optimization of prophylactic treatment could help reduce the burden of HA on patients.

Real-world clinical and psychosocial outcomes among people with mild or moderate haemophilia A treated on-demand in the Italian CHESS II cohort: a real-world data analysis

Abstract Background The burden of severe haemophilia A (HA) has been studied extensively owing to the higher bleeding frequency and associated treatment requirements, leaving a clear unmet need for research focused on the burden of mild and moderate HA. Aims This study sought to characterise the clinical and psychosocial burden of mild and moderate HA in the Italian cohort of the CHESS II study. Methods This was a retrospective analysis of clinical and psychosocial outcomes in a cohort of male adults (≥18 years old) with mild or moderate HA who participated in the cross-sectional CHESS II study (October 2019-November 2020). Treatment patterns, acute and chronic clinical outcomes and mental health indicators were collected via physician-completed forms. Psychosocial outcomes related to impact of HA on social activities, exercise, opportunities, and lifestyle were collected via a participant self-complete questionnaire. All results were reported descriptively. Results A total of 113 people with haemophilia A (PwHA) were included, 79 (70%) with moderate HA and 34 (30%) with mild HA, with mean age of 41.4 and 36.6 years, respectively. No one in the sample was receiving a prophylaxis at the time of data capture, with factor VIII use in the 12 months prior reported in 30% and 29% of moderate and mild PwHA, respectively. Ninety-one PwHA (81%) experienced ≥1 bleeding event in the preceding 12 months. People with moderate HA had higher mean annual bleed rate (2.9 vs. 1.1, respectively) and higher prevalence of chronic pain (74% vs. 35%), anxiety (20% vs. 12%), and/or depression (15% vs. 3%). Target joints were reported in 22% and 12% of moderate and mild PwHA, and problem joints in 51% and 12%, respectively. Of 113 participants, 44 (39%) completed the self-complete form (moderate HA, 57%; mild HA, 43%). Overall, 40% vs. 10% of those with moderate vs mild HA reported reducing or giving up social activities, 44% vs. 21% reducing or giving up exercise, 36% vs. 26% missing out on opportunities, and 48% vs. 26% reported HA impacted their lifestyle. Conclusion Moderate PwHA from the Italian CHESS II cohort appeared to have greater clinical morbidity and lifestyle impact than mild PwHA. Psychosocial outcomes were also worse among moderate PwHA, but significant burden was also observed among mild PwHA. These findings, and the absence of prophylactic treatment in the sample examined, highlight that improving management for potentially undertreated mild/moderate PwHA may aid the avoidance long-term clinical morbidity and negative psychosocial impact.

Factor VIII Use in the Treatment of Breakthrough Bleeds in People with Moderate or Mild Hemophilia A without Factor VIII Inhibitors Receiving Emicizumab Prophylaxis: The Phase III HAVEN 6 Experience

Background: Emicizumab, a bispecific monoclonal antibody that bridges activated factor (F) IX and FX, substitutes for the function of deficient FVIII in people with hemophilia A (HA). Data from the Phase III HAVEN 6 trial (NCT04158648) show a favorable safety profile and efficacy of emicizumab in people with moderate or mild hemophilia A without FVIII inhibitors (Négrier et al. Lancet Haematol 2023). This analysis characterizes the dose and frequency of FVIII and tranexamic acid used for treatment of breakthrough bleeds in people with moderate or mild HA treated with emicizumab during HAVEN 6. Methods: HAVEN 6 is a multicenter, open-label, single-arm, Phase III study designed to assess safety and efficacy of emicizumab in people with moderate or mild HA. The full study design has been published (Négrier et al.). Eligible participants included people of all ages with moderate or mild HA without inhibitors, who warranted prophylaxis as assessed by the investigator. Participants received a standard loading dose of emicizumab 3 mg/kg once weekly for 4 weeks, then a maintenance dose of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks. The lowest FVIII dose required to achieve hemostasis was recommended for breakthrough bleeds. Self-reported bleeds were defined as per the International Society on Thrombosis and Haemostasis (Blanchette et al. J Thromb Haemost 2014); treated bleeds excluded surgical bleeds. Tranexamic acid use in the 24 hours before a surgical procedure was excluded from this analysis. Inferential statistical analyses were not conducted. Results: At the data cut-off (October 30, 2021), 72 participants were enrolled; 51 (70.8%) had moderate HA and 21 (29.2%) had mild HA. Median (range) follow-up was 55.6 (8.7, 89.9) weeks.At baseline, 18 (35.2%) participants with moderate HA and 6 (28.5%) with mild HA had ≥1 target joint ( Table 1). The mean (SD) number of bleeds in the 24 weeks prior to the study was 2.7 (3.1) for those with moderate HA and 9.3 (23.7) for those with mild HA. During the HAVEN 6 study, 48 (66.7%) participants did not experience a treated bleed. Sixteen (31.4%) of the 51 participants with moderate HA and 8 (38.1%) of the 21 participants with mild HA received on-demand FVIII to treat a breakthrough bleed. All participants who experienced a bleed remained on emicizumab, regardless of additional FVIII usage. Of the 71 treated bleeds, 57 (80.3%) were in those with moderate HA and 14 (19.7%) were in those with mild HA ( Table 2). A total of 56 (78.9%) of the 71 treated bleeds were traumatic and 15 (21.1%) were spontaneous. Four participants experienced ≥6 treated bleeds during the study; 28 (90.3%) of the 31 bleeds experienced by these participants were traumatic. Overall, the median (range) number of FVIII infusions per treated bleed was 2 (1, 47) for participants with moderate HA and 1 (1, 6) for those with mild HA. Of the 71 treated bleeds, 54 (76.1%) required 1-2 FVIII infusions. Two participants, both aged 13 years and with moderate HA, had &amp;gt;9 infusions for a bleed. One participant had 19 infusions for a traumatic joint bleed on the finger/thumb. The other participant experienced two traumatic bleeds in the thigh/knee, treated with a total of 47 infusions. The same participant experienced a spontaneous thoracic bleed treated with 19 infusions, a traumatic joint bleed on the left ankle treated with 18 infusions, and a traumatic joint bleed in the finger/thumb treated with 13 infusions. The median (range) cumulative FVIII dose per bleed was 67.1 (31.5, 170.0) IU/kg for those with moderate HA and 47.0 (40.1, 50.5) IU/kg for those with mild HA. The mean (SD) annualized number of infusions per participant was 4.1 (17.2) for those with moderate HA and 2.0 (4.7) for those with mild HA. Seven (13.7%) people with moderate HA and 1 (4.8%) person with mild HA received tranexamic acid, ranging in duration from 1 to 7 days. Tranexamic acid was given for indications including fall with soft tissue bleed, nose bleeds, prophylaxis for dental procedure, and other. No adverse events, including thrombotic events, occurred with concomitant use of emicizumab and tranexamic acid. No desmopressin usage was recorded. Conclusions: Reported bleeds were mainly traumatic and resolved after 1-2 doses of FVIII . No safety concerns were observed with concomitant use of emicizumab and FVIII and/or tranexamic acid. These data may inform breakthrough bleed treatment in people with moderate or mild HA receiving emicizumab.

Emicizumab Prophylaxis in People with Moderate or Mild Hemophilia A Aged ≥40 Years, with and without Comorbidities - Findings from the Phase III HAVEN 6 Study

Background: Emicizumab is a bispecific antibody licensed by the FDA and other regulatory authorities for prophylaxis in people of all ages with hemophilia A (HA) of any severity, with or without factor (F)VIII inhibitors (label varies by country). Few data exist specifically on older people with HA (PwHA), particularly those with comorbidities, such as cardiovascular (CV) conditions, hepatitis, and human immunodeficiency virus (HIV), and in people with moderate or mild HA. Therefore, we present a post hoc analysis of PwHA aged ≥40 years from the HAVEN 6 study (NCT04158648), which was conducted to evaluate the safety and efficacy of emicizumab in people with non-severe HA without FVIII inhibitors. Methods: HAVEN 6 is a global, multicenter, open-label, single-arm, Phase III trial conducted in individuals of all ages with a diagnosis of moderate (FVIII activity ≥1%-≤5%) or mild (FVIII &amp;gt;5%-&amp;lt;40%) HA without FVIII inhibitors, warranting prophylaxis as assessed by the investigator (Negrier et al. Lancet Haematol 2023). As a loading dose, emicizumab was administered subcutaneously once weekly at 3mg/kg for 4 weeks. This was then followed by the participant's choice of maintenance dose, which included the options of 1.5mg/kg weekly, 3mg/kg every 2 weeks, or 6mg/kg every 4 weeks. The primary study objective was safety, including thromboembolic events (TEs) and thrombotic microangiopathy (TMA). The primary efficacy endpoint was the annualized bleed rate (ABR) for treated bleeds. An age cut-off of ≥40 years was selected for this exploratory analysis in order to obtain a population with a high proportion of PwHA with comorbidities. In this analysis, comorbidities included CV risk factors (past medical history of CV disease; hypertension; hyperlipidemia; diabetes; body mass index ≥30kg/m 2), HIV, and current or previous history of hepatitis C virus (HCV) infection. Results: At data cut-off (Oct 30, 2021), 72 participants were enrolled in HAVEN 6. Of these, 16 individuals were aged ≥40 years and were included in this analysis; among the 16 participants aged ≥40 years, 8 (50%) were aged ≥50 years. The median (range) age was 50.5 (41-71) years and all were male. Ten (62.5%) participants had moderate HA and 6 (37.5%) had mild HA. Prior to study entry, 6 (37.5%) participants had been receiving prophylactic FVIII, while the other 10 (62.5%) had been receiving episodic FVIII infusions. In the 24 weeks prior to study entry, the median (range) number of bleeds reported by these 16 participants was 3.5 (0-60) and the mean (SD) was 7.4 (14.5), with two individuals experiencing ≥9 bleeds. Nine (56.3%) of the 16 participants had at least one CV risk factor, with 5 (31.3%) having two or more. Three (18.8%) individuals had HCV only, 1 (6.3%) had HIV only, and 2 (12.5%) had HCV and HIV co-infection. Five (31.3%) of the 16 participants did not have any of the comorbidities defined in this analysis. At the data cut-off, the median (range) duration of emicizumab exposure for the 16 participants aged ≥40 years was 1.09 (0.61-1.72) years. Fifteen (93.8%) of the 16 participants experienced ≥1 adverse event (AE) during the study. Three (18.8%) individuals experienced a serious AE and 1 (6.3%) a Grade 3/4 AE; all were deemed unrelated to emicizumab ( Table 1). There were no fatal AEs, AEs leading to withdrawal from treatment or dose modification/interruption, or TMAs. One individual, who had no CV risk factors or HIV/HCV infection, experienced a TE (Grade 1 thrombosed hemorrhoids); this was deemed unrelated to emicizumab. Three participants experienced a total of six treatment-related AEs; three of these were local injection-site reactions, with the other three being fatigue, head discomfort, and accidental overdose. During the study, the mean (95% confidence interval) ABR for treated bleeds for the 16 participants aged ≥40 years was 1.03 (0.03, 5.62), which is similar to that recorded for the overall population of HAVEN 6 (0.94 [0.02, 5.48]; Table 2). A total of 11 (68.8%) participants had zero bleeds during the study, which is comparable with the 66.7% reported for the total population. Conclusions: The small number of individuals aged ≥40 years included in the current analysis is a limitation that precludes drawing firm conclusions from the data. However, the safety and efficacy of emicizumab in these participants did not differ notably from those observed in the overall population of people with moderate or mild HA in HAVEN 6.

Proactive Systematic Hemophilia Carrier Screening: A Step Towards Gender Equity in Hemophilia Care

Introduction Despite multiple awareness-raising initiatives, and in contrast with male persons with hemophilia (PwH), a considerable number of carriers and female PwH still go undiagnosed. We here present the findings of a proactive and extensive hemophilia carrier screening project. Methods From May 2021 until April 2023, potential and obligate carriers of hemophilia A (HA) and B (HB) were identified by updating family trees of all PwH regularly followed at the Cliniques universitaires Saint-Luc. Data from previously screened female individuals (bleeding history, coagulation factor assays and testing for the index patient's pathological genetic variant) were collected retrospectively through electronic medical records (EMRs). Female individuals who had not been previously screened or with missing data were provided with a total of 125 invitation letters by related index hemophilia patients. The study protocol received approval of the local ethics committee. Results All 287 male PwH (226 HA, 61 HB) from 228 families (180 HA, 48 HB) were included in the analysis. Seven female PwH (3 HA, 4 HB) were considered as index cases in their families. In total, based on the family trees, there were 900 females, among which 454 were obligate and/or genetically proven carriers of hemophilia and 118 were found to be non-carriers (Figure 1). Mean age at diagnosis was 30.7 years (range 1-82) in families with HA and 30.1 years (range 0.5-93) in families with HB, without significant difference between these two groups (p=0.809) or between families with severe, moderate or mild hemophilia (p=0.535). Genetic testing for pathological variants has been conducted in 133 obligate, 237 potential and 4 sporadic carriers, and remains to be performed in 190 obligate and 328 potential carriers. Eight females were obligate non-carriers. The group of mothers, sisters and daughters of PwH comprised 543 females, of which at least 178 (35.7% of those with known date of birth) were of reproductive age (18-49 years). Seventy-three percent of females in the latter group have had genetic testing. The proportion of female individuals genetically tested did not significantly differ between families of different severities of HA (p=0.132). In families with moderate HB, female individuals were more likely to be tested (genetic status known in 59.4%) than in other HB severity groups (p=0.01), yet this may be attributed to the presence of one large family comprising 6 male persons with moderate HB and 22 female individuals, of whom a large proportion (n=18, 82%) has had genetic testing. Among carriers with known coagulation factor levels (261/454), 42 (23.0%) and 23 (29.5%) carriers of HA and HB, respectively, had a factor level below 40 IU/dL, and 65 (35.5 %) and 32 (41.0%) had a factor level below 50 IU/dL. The proportion of carriers with a factor level below 40 IU/dL did not significantly differ between families with severe, moderate and mild hemophilia (22.6%, 34.7% and 22.7% respectively, p=0.213), neither did mean coagulation factor levels in carriers with a factor deficiency in these groups (26.2, 30.4 and 27.1 IU/dL in families with severe, moderate and mild HA and HB, p=0.344). Carriers with a coagulation factor deficiency of less than 40 IU/dL were screened earlier than other female individuals (mean age at diagnosis 25.8 and 31.8 years, respectively, p=0.034). Conclusions This study represents the first reported attempt to systematically identify all (potential) hemophilia carriers within families of all PwH followed at a single hemophilia treatment center. To date, this initiative has allowed 44% of the entire cohort to be screened, and carrier status to be genetically confirmed in 73% of mothers, sisters and daughters of PwH who are of childbearing age, based on the date of birth documented in their EMR. Although original and promising, these data reflect the major challenges and difficulties in reaching out and providing appropriate screening to all women genetically linked to one or more PwH. The carrier screening efforts that have been initiated in our center, and which should ideally be replicated across the hemophilia community globally, appear as a critical step towards providing equal access to haemophilia diagnosis and care to all potentially affected individuals, regardless of their gender.

Minimum factor VIII levels to prevent joint bleeding in mild hemophilia A

AbstractThe severity of the bleeding phenotype in patients with hemophilia A (HA) broadly correlates with the degree of coagulation factor VIII (FVIII) deficiency in plasma. However, the FVIII level necessary to achieve the goal of zero joint bleeds remains unclear. This study aimed to identify the minimum FVIII level necessary to prevent joint bleeds in patients with HA. In this retrospective study, patients with congenital mild HA treated on demand, aged ≥16 years, with no history of FVIII inhibitors, followed at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center in Milan, were enrolled. We investigated 270 male patients with a median age of 45 years (16-88) and median lifelong FVIII of 21 IU/dL. One hundred patients (37%) had a lifelong history of at least 1 joint bleed. The mean annualized joint bleeding rate (AJBR) and spontaneous AJBR were 0.016 (standard deviation [SD], 0.032) and 0.001 (SD, 0.010), respectively. After adjusting for age, for each IU/dL increase in FVIII, there was a 6% reduction in AJBR and an 11% reduction in spontaneous AJBR. The minimum FVIII levels needed to prevent lifelong any joint bleeds and spontaneous joint bleeds resulted to be 19.2 IU/dL and 17.7 IU/dL, respectively. In this large cohort of persons with mild HA, we identified the minimum FVIII levels needed to prevent total and spontaneous joint bleeds (19.2 IU/dL and 17.7 IU/dL, respectively). These findings could suggest important implications for the accurate design of prophylactic therapies for persons with moderate and severe HA, including gene therapy.

Antidrug antibodies against the polyethylene glycol moiety inhibit the procoagulant activity of therapeutic polyethylene glycolated factor VIII

BackgroundThe standard therapy for patients with hemophilia A (HA) is the replacement with factor VIII (FVIII) therapeutics. To overcome the limitation of short half-life of wild-type FVIII protein, polyethylene glycol (PEG) can be coupled to therapeutic FVIII to improve pharmacokinetics. ObjectivesWe aimed to characterize antibodies developed against a FVIII therapeutic PEGylated with a 40-kDa PEG (40PEG-BDDFVIII) in 2 patients with mild HA. MethodsAn inhouse bead-based immunoassay was developed to characterize and confirm the specificity of the detected antibodies. The neutralizing nature of the antibodies toward PEGylated therapeutics was determined by a modified Nijmegen-Bethesda assay. ResultsTwo out of 46 patients treated with 40PEG-BDDFVIII developed inhibitory antibodies toward the drug. Switching to a non-PEGylated FVIII successfully increased the FVIII activity in both patients. In patient 1, antibodies were raised against FVIII and PEG. Anti-FVIII antibodies were of the immunoglobulin (Ig)G isotype, whereas anti-PEG antibodies were of IgG, IgM, and IgA isotypes. In patient 2, antibodies of IgG and IgA isotypes were directed only against the PEG moiety. Competitive assays confirmed the specificity of the antibodies against PEG. The applied Nijmegen-Bethesda assay revealed that patients’ anti-PEG antibodies and AGP3, an antibody against the backbone of PEG, can inhibit all currently available PEGylated therapeutics but to different degrees. No inhibitory FVIII antibodies were detected. ConclusionAntibodies against the PEG moiety of 40PEG-BDDFVIII abolished the efficacy of the drug. This is the first report on real-world experiences with the development of neutralizing anti-PEG antibodies after treatment with PEGylated FVIII therapeutics in mild HA.

FVIII inhibitor surveillance in children with hemophilia A in Indonesia: a report from the Indonesian Pediatric Hematology-Oncology Working Group.

Factor VIII (FVIII) inhibitor diagnosis and surveillance in Indonesia are challenging owing to geographic conditions and the lack of laboratory facilities nationwide for inhibitor assays. This study aimed to determine the prevalence of FVIII inhibitors in children diagnosed with hemophilia A (HA) in Indonesia. A cross-sectional study was conducted in 12 hospitals in eight provinces of Indonesia between 2020 and 2021. Factor VIII inhibitor screening was performed in a central hemostasis laboratory for all children with HA (≤18 yr) who had received a minimum of 10 exposure days to clotting factor concentrates. The FVIII inhibitor titer was determined using the Bethesda assay. Children (388) were enrolled in this study, including 219 (56.4%), 131 (33.8%), and 38 (9.4%) with severe, moderate, and mild HA, respectively. The prevalence of children who developed FVIII inhibitors was 37 out of 388 (9.6%). Factor VIII inhibitors were found in 25/219 (11.4%) severe, 11/131 (8.3%) moderate, and 1/38 (2.6%) children with mild HA. Thirteen children had low-titer inhibitors and 24 had high-titer inhibitors, with a median of 9.44 (1.48‒412.0) Bethesda Units. Among 13 children with low-titer inhibitors, eight underwent a confirmation test, of which five tested negative and were classified as transient. A significant difference in annual joint bleeding rate was found between patients with low and high inhibitor titers and those without inhibitors (P＜0.001). Factor VIII inhibitor prevalence in Indonesia was relatively low. However, the risk factors that may contribute to FVIII inhibitor development among Indonesian patients require further study.

The activated partial thromboplastin time-clot waveform analysis in hemophilia: Does it help in differentiation?

The clot waveform analysis (CWA) provide valuable information beyond clotting time. The present study was planned to assess whether the activated partial thromboplastin time (aPTT)-CWA can differentiate between hemophilia A (HA), hemophilia B (HB), or hemophilia A with inhibitors (HAWI). The aPTT-CWA was generated by an optical detection system (ACL-TOP™ 500 coagulation analyzer) and the other tests were performed as per instructions from the manufacturer in the kit. A total of 75 samples (47-HA, 16-HAWI, and 12-HB) with prolonged aPTT were recruited. On analyzing the quantitative aPTT-CWA data of HA (non-inhibitors) and HB samples, the width of acceleration 1 [+] peak was the differentiating finding. Among the significant parameters, the second derivative [+] peak was lower in both mild and moderate HA, equating to HB. The time for the height of 1/2 fibrin formation and width of velocity was significantly higher in mild, moderate and severe HA. The study did not show any significant differentiating finding while comparing HAWI and hemophilia A non-inhibitors (HANI). In the subgroups of HAWI and HANI with aPTT <70 s and 70-100 s, the second derivative [+] peak (2A) was higher and the time for the height of 1/2 fibrin formation (1C) was lesser in HAWI. The aPTT-CWA parameters may be supportive for the differentiation of hemophilia including its severity and the existence of inhibitors.

Characteristics and Healthcare Utilization of Patients with Mild or Moderate Hemophilia A in the US - an Analysis from the Picnichealth Cohort

Background: People with mild or moderate hemophilia A (HA) constitute 40-52% of all people with HA; nonetheless, they are a poorly characterized population in real-world data and published literature (Witkop et al. Blood 2021). To better understand this population, we used a novel platform, PicnicHealth, which integrates real-world data from patients' medical records and patient-reported outcomes, including bleeding occurrence, treatment for bleeds, and pain (Skinner et al. Blood 2021; Witkop et al. Blood 2021). We aim to study the epidemiology of mild and moderate HA and evaluate the effects of various demographic variables and the COVID-19 pandemic on use of healthcare facilities. Methods: People with HA (PwHA) have been enrolled into the PicnicHealth online record management platform since June 2020. Inclusion criteria for this cohort with mild or moderate HA were based on baseline factor (F)VIII activity level (mild, >5-50%; moderate, 1-5%). Records were collected from all known healthcare providers and facilities, including hematology, primary care, and other specialty care, in addition to laboratory reports, imaging reports, pathology, and any inpatient or outpatient encounter since the diagnosis. Descriptive statistical analyses were performed to summarize cohort characteristics. Results: As of June 2022, there were 113 PwHA enrolled in PicnicHealth who met the inclusion criteria for this analysis, of whom 68 (60.2%) had mild HA and 45 (39.8%) had moderate HA. In total, 90 (79.6%) participants were male and 23 (20.4%) were female. The majority identified as 'White' (n=77; 68.1%), followed by 'More than one race or unreported' (n=25; 22.1%), 'Black or African American' (n=8; 7.1%), and 'other race' (n=3; 2.7%). The median age at diagnosis was 12.5 years (Q1, Q3: 1.96, 29.8). Only 8 participants (7.1%) had evidence of FVIII inhibitors during their lifetime. The median (Q1, Q3) Hemophilia Joint Health Score was 4.00 (3.00, 9.00) and the median (Q1, Q3) annualized bleed rate was 0.17 (0, 3.63). In terms of treatment, in the 2 years prior to enrollment, 36 (31.9%) participants had received FVIII prophylaxis, 73 (64.6%) had received FVIII on demand, and 10 (8.8%) had received emicizumab (Table 1). In the 2 years prior to enrollment, participants with mild or moderate HA visited a healthcare facility a median (Q1, Q3) of 7 (4, 11) times and a hematology practitioner a median (Q1, Q3) of 2 (1, 3) times. The majority of the visits to hematology practitioners were to medical doctors (93%), with a smaller number to nurse practitioners or allied health professionals (7%). There was no notable difference in the median number of visits to healthcare facilities or hematologists according to disease severity, race, or inhibitor status. The five states with the highest number of healthcare facility visits by hemophilia patients were California (24.7%), Indiana (7.1%), Michigan (5.9%), Texas (5.9%), and Virginia (4.3%). Finally, we assessed the impact of the COVID-19 pandemic on participants' visits to healthcare facilities. Between January 2019 and July 2021, there were no apparent changes to emergency care visits. For routine care visits, there have been variations since the pandemic began, which may be attributable to lockdown restrictions, although the number of these does not strictly correlate with COVID-19 case numbers (Figure 1). The study is limited by potential bias resulting from participant reporting and the retrospective nature of data collection. Conclusions: Our study provides valuable insights into the characteristics and utilization of healthcare of the under-represented cohort of people with mild or moderate HA. We found notable variation in the geographical distribution of healthcare facilities and visits by PwHA across different states. As expected, routine visits by patients fluctuated during the COVID-19 pandemic. The data generated from this study may aid planning for, and delivery of, the most appropriate and effective care for this group of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characteristics and Bleeding Behavior of Females with Mild Hemophilia A: Longitudinal Study from Picnichealth Hemophilia A Database

Background: Hemophilia A (HA) is an X-linked condition characterized by factor VIII (FVIII) levels below the normal range, leading to excessive bleeding. Disease severity can be categorized as mild (FVIII: >5-40%), moderate (FVIII: 1-5%) or severe (FVIII: <1%) (Blanchette et al. J Thromb Haemost 2014). Females represent a minority of patients with HA and their bleeding phenotypes are poorly characterized in scientific literature. In this retrospective cohort study, the real-world, patient-centric PicnicHealth database, which integrates clinical data with patient-reported outcomes, is used to examine the epidemiology and bleeding phenotype in females with mild HA (FwHA) compared with a cohort of males with mild HA (MwHA). Methods: FwHA and MwHA have been recruited since June 2020 in the United States. Severity of HA was based on physician-reported provider notes, or baseline FVIII levels if provider notes were inconclusive (for this analysis, mild HA was defined as FVIII >5-50%). Demographics, disease characteristics, and patient-reported outcomes were collected. Bleeding phenotype was assessed up to a year prior to enrollment and described according to bleed etiology (i.e., traumatic, spontaneous, procedure-related, unknown), bleed frequency, and bleed management (use of FVIII concentrates). A two-tailed test was used to analyze differences between the cohorts, with p<0.05 considered significant. Results: At data cut-off on May 31, 2022, 68 patients with mild HA had been recruited: 23 FwHA and 45 MwHA (Table 1A). There were no differences in racial demographics, with approximately 70% identifying as 'White' in both groups. The median FVIII level was significantly higher in the female cohort at 26% (Q1, Q3: 17, 36%), compared with the male cohort at 10% (Q1, Q3: 6, 13%; p=<0.001). Median (Q1, Q3) age at first diagnosis was also significantly higher in the female cohort, at 24.3 (8.71, 36.0) years, compared with the male cohort, at 10.5 (1.02, 21.4) years (p=0.048). However, after adjusting for median FVIII levels, the difference in age at first diagnosis was not statistically significant (p=0.56) between males and females. Median (Q1, Q3) follow-up periods available from medical records were similar for FwHA and MwHA (8.92 [5.60, 12.9] years and 9.22 [4.27, 12.4] years, respectively). FVIII inhibitors were not identified in any FwHA but were present in 13.3% of MwHA. The majority of patients’ records had no evidence of HIV, hepatitis B, or hepatitis C status; however, 5.9% of MwHA were reported to be positive for hepatitis B and C, compared with no FwHA. Prevalence of iron deficiency anemia was higher in FwHA compared with MwHA, at 27.7% vs. 6.7% (significance not assessed due to low numbers). Access to hemophilia treatment centers was numerically higher for FwHA compared with MwHA (82.6% vs. 73.3%), but this difference was not significant. Evaluation of bleeding phenotype in the female and male cohorts is described in Table 1B. The small number of recorded events does not allow for meaningful conclusions about the differences in bleeding phenotypes between females and males with mild disease. The proportion of FwHA treated with FVIII prophylaxis (30.4%) was numerically lower than the MwHA (40.0%), but not statistically significant (p=0.611). For patients on prophylaxis in the year before enrollment, the median (Q1, Q3) number of days on prophylaxis was 209 (149, 268) days for FwHA and 365 (168, 365) days for MwHA (significance not assessed due to low numbers). On-demand FVIII concentrate usage was similar in both groups with 47.8% of FwHA and 51.1% of MwHA receiving FVIII. Conclusions: This real-world cohort study observed differences in disease characteristics between FwHA and MwHA, but statistical analysis was limited by low participant numbers. FwHA had higher baseline FVIII levels compared with MwHA. On-demand use of FVIII concentrates was comparable between the cohorts. Recorded bleeding events were too low in number to draw conclusions regarding bleeding phenotype. As this database relies on patient participation, there was a potential selection bias towards those with more symptomatic disease, and some data were incomplete. Future studies will analyze ongoing prospective data, collect more granular data on bleeding phenotype, and conduct comparative analyses of cohorts stratified by baseline FVIII levels. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Discrepancy between the Results of One-Stage and Chromogenic Factor VIII Assays: Switch in Diagnosis from Mild to Moderate Hemophilia a in Three Cases

Introduction Factor VIII (FVIII) activity can be measured with different methods including one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). Some persons with mild hemophilia A (HA) have a significant discrepancy between the assays which has been previously reported. Discrepancy between these two methods, albeit less frequent, can also lead to a switch in diagnosis from mild to moderate HA. Herein, we report 3 persons with HA (PwHA) whose diagnosis changed from mild to moderate HA after obtaining FVIII levels assessed by CSA. Materials and Methods Data were extracted from the medical records of the PwHA including demographics, bleeding rates, and factor levels. FVIII activity was measured using the OSA on an ACL Top 500 with SynthaSil aPTT reagent (Instrumentation Laboratories Bedford, MA, USA). Factor VIII activity was also determined photometrically via the Chromogenix Coatest® SP4 FVIII chromogenic assay kit (bovine chromogenic FVIII activity, Diapharma Group, West Chester, OH). Results Data were collected from 3 PwHA who were previously diagnosed with mild HA yet were noted to have a bleeding phenotype worse than expected for mild HA (Table-1). Case 1 is 26 years old and had been experiencing multiple joint bleeds. His OSA FVIII level was 6.8%. He was on clotting factor concentrate (CFC) on demand. After having severe hemophilic arthropathy affecting his social life, prophylaxis with CFC was commenced. Significant improvement was observed after the initiation of prophylaxis. His CSA FVIII level was 2.7%, consistent with his bleeding phenotype, and he has been on emicizumab prophylaxis for a year without any bleeding events. Case 2 is 22 years old and had been experiencing frequent muscle bleeds. His OSA FVIII level was 6.1% and CSA FVIII level was 2.7%. He remains on CFC on demand based on his preference despite the frequent bleeding. Case 3 is 15 years old and was diagnosed with mild HA at the age of 8 after recurrent joint bleeds. His OSA FVIII level was 13.8% and CSA FVIII level was 1.5%. He has been on emicizumab prophylaxis for 10 months without any bleeding event. Conclusion While discrepancies between assays in mild hemophilia have been widely reported, there are fewer reports on an assay discrepancy changing a diagnosis from mild to moderate HA. As such, we strongly suggest performing both OSA and CSA for the diagnosis and classification of HA especially if the PwHA has more bleeding episodes than expected. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Unravelling the Effect of Blood Type on FVIII:C Levels and Response to DDAVP in 20 Males with a Single Genotype (Twillingate Variant) Causing Mild Hemophilia Α

Introduction: Hemophilia A (HA) occurs secondary to >1000 variants in the F8 gene resulting in decreased/absent production of factor (F) VIII. FVIII:C (coagulant) levels in persons with mild/moderate HA are most impacted by their genotype. ABO blood type (BT) may also impact endogenous FVIII:C levels, but this impact is difficult to assess in a genetically heterogenous group of HA subjects. Canada has a population of mild-moderate HA secondary to a unique large single genotype: c.6104T>C, p.Val2035Ala. This variant arose from a founder effect that occurred about 200 years ago in Twillingate, Newfoundland. We hypothesized that subjects with the Twillingate genotype (despite having the same genotype and thus producing similar amounts of FVIII) would show different endogenous FVIII:C levels related to their BT, as BT impacts FVIII (and VWF) clearance. Our study objectives were to understand the impact of BT on endogenous FVIII:C levels whilst controlling for genotype, and to explore the impact of BT on DDAVP responsiveness. Methods: This was a retrospective, single-center cohort study. Males with a confirmed Twillingate genotype treated at our center between 1980-01-01 to 2022-03-01 were eligible. For each subject, ABO BT, VWF antigen (Ag) and activity, and FVIII:C levels were determined by chart review. We recorded the lowest FVIII:C baseline level; for subjects who had >1 FVIII:C level (done in a non-bleeding state) we also determined their mean baseline FVIII:C level. For DDAVP challenges, the age at the challenge, dose, and route of administration were recorded, as well as pre and 1-hr post FVIII:C levels. Based on 1-hr post-DDAVP FVIII:C levels (IU/mL), subjects were classified on their DDAVP response as responders (≥0.50), partial responders (0.30 to 0.49), or non-responders (<0.30). Median, IQR, mean, and SD were calculated for baseline FVIII:C and VWF:Ag levels, stratified by age (<12; ≥12 y) and by BT (O; non-O). T-tests and Mann-Whitney U (MWU) tests were used to compare normally and non-normally distributed data, respectively. The Fisher-Freeman-Halton Exact Test was used to compare responses to DDAVP between O and non-O subjects. Statistical significance was considered as p≤0.05. All analyses were performed using IBM SPSS Statistics Version 28. Results: 20 males were included: 9 were O BT and 11 were non-O BT (10 were A, 1 was B). There were statistically significant differences between the 2 ABO groups in their median lowest FVIII:C levels: 0.05 IU/mL (O BT) vs. 0.08 IU/mL (non-O BT); p=0.05 (MWU) and in mean FVIII:C levels: medians: 0.08 IU/mL (O BT) vs. 0.12 IU/mL (non-O BT); p=0.02 (t-test). Too few subjects had FVIII:C levels reported at ≥12 y of age to perform statistical analyses. Fifteen subjects (8 O BT: 7 non-O BT) underwent a DDAVP challenge; 13 performed at our center and 2 elsewhere. Median 1-hr post-DDAVP FVIII:C levels were 0.32 IU/mL (O BT) and 0.43 IU/mL (non-O BT); p=0.04 (t-test). The absolute FVIII:C increase with DDAVP was not statistically different between the 2 groups: median increase of 0.22 IU/mL (O BT) vs. 0.28 IU/mL (non-O BT); p=0.10 (t-test) nor was the FVIII:C fold increase: median increase 3.3-fold (O BT) vs. 3.3-fold (non-O BT); p=0.51 (t-test). Among O BT subjects, none were responders, 5 were partial responders and 3 were non-responders. In the non-O BT subjects, 2 were responders and 5 were partial responders. The variation in response between the 2 groups failed to achieve statistical significance (p=0.14). Given uncertainties in DDAVP challenges (e.g. dose, route of administration) done elsewhere, we also analyzed the DDAVP challenge results just for the 13 subjects from our center. The median 1-hr post-DDAVP FVIII:C levels were 0.30 IU/mL in 7 O BT subjects and 0.45 IU/mL in 6 non-O BT subjects; p=0.02 (t-test). Conclusions: This study shows that in HA subjects with an identical genotype, BT significantly impacts FVIII:C levels. Although only 1 unique genotype was studied, we believe that other hemophilic variants leading to mild HA will behave similarly. This may explain why in subjects with mild HA, there is an overrepresentation of O BT. Persons with non-O BT and HA variants that only slightly reduce FVIII production may have FVIII:C levels that are not as reduced and thus may never present with bleeding and be diagnosed with HA. In contrast, if such persons have O BT, they are likely to show much lower FVIII:C levels and thus more likely to bleed and be diagnosed with HA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Inhibiting Activated Protein C Cleavage of Factor VIII for Hemophilia a Gene Therapy

Background Despite progress in adeno-associated virus (AAV) mediated factor VIII (FVIII) gene transfer for hemophilia A (HA), durable and sustained FVIII expression sufficient to ameliorate bleeding in all participants is an unrealized goal. Following the success of using the gain of function FIX-Padua variant in hemophilia B gene therapy, we hypothesized that use of an enhanced hemostatic function FVIII would similarly improve HA gene therapy by: 1) permitting use of lower vector doses, thereby overcoming dose-dependent safety and efficacy limitations and 2) achieving efficacy with lower FVIII antigen. We previously published a FVIII variant resistant to activated protein C (APC) cleavage (FVIII-R336Q/R562Q or FVIII-QQ) with normal specific activity and 4-5 fold improved hemostatic function in recombinant protein experiments (Wilhelm et al. Blood 2021). Aims We evaluated the possible clinical translation of FVIII-QQ for HA AAV-mediated gene therapy by determining the hemostatic benefit and potential prothrombotic and immunological risks in mice. Additionally, FVIII-QQ steady-state expression was 2.5 to 5-fold higher than FVIII-WT. We hypothesized this was due to disrupted cleavage by APC or other serine proteases at R336 and/or R562. Results Survival studies in HA/CD4KO and WT/CD4KO mice treated with AAV vectors to express (h)uman FVIII-WT and hFVIII-QQ in the range of mild HA, normal, and supratherapeutic FVIII levels thus far demonstrate no significant differences in survival at 7-11 month follow up or D-dimer levels after 8 months. Additionally, FVIII-QQ mice were generated using CRISPR/Cas9 to introduce R562Q (WT mice are Q336) for endogenous (m)ouse FVIII-QQ expression. Endogenous mFVIII-QQ mice were viable, fertile, normal weight, and D-dimers did not significantly differ from WT mice, while FVIII activity was ~2-fold higher than WT mice. HA immune competent mice treated with either 6 weekly doses of hFVIII-WT or hFVIII-QQ protein (0.2 μg) or AAV vector to express hFVIII-QQ or hFVIII-WT had no significant differences in inhibitor titers. To evaluate hemostasis, HA/CD4KO mice were treated with AAV vector only differing by 2 amino acids (R336, R362) at 3 different doses (n=6-12 mice/cohort) to express hFVIII-QQ or hFVIII-WT and underwent tail clip challenge. Estimated EC50 and EC80 of vector doses required to normalize blood loss to WT mice were 5 and 10-fold lower, respectively, for hFVIII-QQ versus hFVIII-WT supporting a hemostatic benefit to using the hFVIII-QQ transgene. Interestingly, across 3 different vector constructs differing only by F8 codon optimization, we observed hFVIII-QQ antigen values 2.5 to 5-fold higher than in mice expressing hFVIII-WT. Analysis of liver tissue from HA/CD4KO mice treated with the same vector construct and dose to express hFVIII-WT or hFVIII-QQ demonstrated approximately the same mRNA values, but plasma hFVIII-QQ antigen was 4-fold higher than hFVIII-WT and intracellular hFVIII-QQ antigen was the same or lower than hFVIII-WT antigen. Consistent with our in vivo AAV experiments, preliminary studies of intracellular versus secreted hFVIII antigen in BHK stable cell lines expressing hFVIII-WT or hFVIII-QQ demonstrated similar mRNA values with higher relative secreted hFVIII-QQ protein. To further probe the mechanism of higher hFVIII-QQ steady-state expression, we evaluated a panel of serine proteases (APC, FIXa, FXa, plasmin, PACE/furin and thrombin) for cleavage of FVIII-QQ relative to FVIII-WT protein. As expected, hFVIII-QQ was resistant to APC cleavage. Surprisingly, all other serine proteases tested demonstrated cleavage of hFVIII-WT, but not hFVIII-QQ, at R336 and/or R562 suggesting protease attack at these cleavage sites may occur more than previously appreciated, though the physiologic significance remains to be determined. Conclusion Our studies outline the use of hFVIII-QQ transgene expression thus far does not demonstrate safety concerns and confers hemostatic benefit over hFVIII-WT via: 1) improved hemostatic function and 2) higher steady-state expression. Enhanced steady state hFVIII-QQ expression relative to hFVIII-WT was observed across multiple model systems. Preliminary data demonstrate multiple serine proteases can cleave at the described FVIII APC cleavage sites (R336, R562) suggesting hFVIII-QQ may generally be more proteolytically stable thereby permitting improved steady-state expression.

Long-Term Durable FVIII Expression with Improvements in Bleeding Rates Following AAV-Mediated FVIII Gene Transfer for Hemophilia A: Multiyear Follow-up on the Phase I/II Trial of SPK-8011

Background: Hemophilia A (HA) is an inherited blood disorder caused by deficiency or dysfunction of factor (F)VIII. The disease is characterized by recurrent bleeding, particularly into joints, which often results in arthropathy and functional disability. HA is currently managed with intravenous (IV) infusions of replacement FVIII or non-factor replacement therapy such as emicizumab. More recently, gene therapy, involving the use of a recombinant adeno-associated viral (AAV) vector to target hepatocytes, with the aim of safely imparting long-term stable FVIII expression to prevent bleeding, is being investigated for HA. SPK-8011 is an investigational AAV vector optimized to achieve clinically relevant and durable hepatocyte-derived FVIII expression at the lowest possible vector dose. Methods: This Phase I/II trial (NCT03003533/NCT03432520) of SPK-8011 is an open-label, multicenter, non-randomized trial, the full methodology of which has been reported previously (George et al. N Engl J Med 2021). Eligible participants were males ≥18 years of age, with FVIII levels ≤2%, >150 exposure days to FVIII concentrates, and no FVIII inhibitors. All participants were negative for neutralizing antibodies to SPK200. Participants were enrolled into four dose cohorts receiving a single IV dose of either 5×1011, 1×1012, 2×1012, or 1.5×1012 vector genomes (vg) per kilogram of body weight, with a maximum dose based on a BMI of 30 kg/m2. Several immunomodulation (IM) approaches were evaluated. Trial objectives included evaluation of the safety and efficacy of SPK-8011 and the extent and durability of FVIII expression. Results: At data cut-off (30 June 2022), 23 participants were included across dosing cohorts of 5×1011 vg/kg (n=2), 1×1012 vg/kg (n=3), 1.5×1012 vg/kg (n=9), or 2×1012 vg/kg (n=9). Median (range) observation time was 159.3 (6.9-259.9) weeks, based on both the primary study 8011-101 and the long-term follow-up study. A total of 49 treatment-related adverse events (AEs) were reported; 23 were considered vector-related, including one serious adverse event (Grade 2 alanine transaminase [ALT] elevation resulting in elective hospitalization for IV corticosteroid administration), and 26 were related to IM therapies. No FVIII inhibitors or thrombotic events were reported. Transient non-sustained asymptomatic ALT elevation occurred in 11 participants during the expected window of presumed capsid immune response and resolved with use of IM agents. In 16 participants with ≥1 year follow-up, a one-stage FVIII assay showed no apparent decrease in FVIII activity over time, with a majority expressing in the mild HA range (Table). Sustained expression of FVIII was maintained in 21/23 participants with several methods of IM; two participants lost FVIII expression following a presumed capsid immune response (George et al. N Engl J Med 2021). Across all 21 participants with sustained FVIII expression, a 91% (95% CI: 78-97%) reduction in annualized bleeding rate (ABR) for all bleeds was observed, with all-bleed ABR of 11.59 (7.39-18.17) before infusion vs. 0.99 (0.46-2.14) after infusion (Figure). The 16 participants on prophylactic treatment before gene therapy had an 82% (95% CI: 53-93%) reduction in ABR for all bleeds; 6.88 (4.16-11.36) before vs. 1.26 (0.57-2.77) after infusion. ABRs for spontaneous bleeds were 5.20 (2.99-9.04) and 0.52 (0.19-1.39) before and after infusion, respectively. The five participants using on-demand treatment before infusion had a 99% (95% CI: 98-100%) reduction in all-bleed ABR; 27.26 (18.80-39.53) vs. 0.20 (0.09-0.45) before and after infusion, respectively, and 20.98 (12.29-35.82) vs. 0.05 (0.01-0.29) for spontaneous bleeds. In total, 17/21 (81%) participants had an ABR of <1 for treated bleeds and 20/21 (95%) had an ABR of <1 for spontaneous treated bleeds following infusion of SPK-8011. Median (IQR) annualized FVIII infusion rates (AIRs) of 0.2 (0.0-1.2) were reported across all participants 28 days post vector infusion vs. 82.0 (36.0-106.0) before vector administration. Conclusions: With up to 5 years of follow-up, a single infusion of SPK-8011 resulted in durable year-to-year FVIII expression and clinically meaningful reductions in ABR and AIR. No major safety signals were reported, indicating SPK-8011 was well tolerated in this population of people with HA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Subgroup Analysis of the Effectiveness and Safety of Damoctocog Alfa Pegol Prophylaxis in Previously Treated Patients with Hemophilia A Treated Every 5 or Every 7 Days: Results from the Real-World Observational HEM-POWR Study

Background: Extended half-life (EHL) FVIII products have been developed to reduce the burden of frequent intravenous infusions for people with hemophilia A (HA). Damoctocog alfa pegol is an EHL PEGylated B-domain-deleted recombinant FVIII concentrate approved for use in previously treated patients (PTPs) aged ≥12 years with HA. The recommended initial prophylactic dosing regimen in the USA is twice weekly, which may be adjusted to every 5 days (E5D) and can then be individually tailored to less or more frequent dosing based on bleeding episodes (FDA 2018). The safety and efficacy of extended dosing intervals were demonstrated in the pivotal PROTECT VIII studies (Reding et al, Haemophilia 2021). Real-world safety and effectiveness of damoctocog alfa pegol administered with any dosing regimen has been reported in the previously presented interim analyses of the HEM-POWR study (Reding et al., ISTH 2021, 2022). However, separate analyses of E5D or every-7-day (E7D) prophylaxis regimens in the real-world have not yet been reported. Objective: Post hoc analysis to explore the safety and effectiveness of extended dosing with damoctocog alfa pegol in PTPs receiving prophylactic treatment in the ongoing real-world HEM-POWR study. Methods: HEM-POWR (NCT03932201) is a prospective, multinational, observational open-label Phase IV cohort study of damoctocog alfa pegol in PTPs with mild, moderate, and severe HA. Patients in this subgroup analysis received prophylactic damoctocog alfa pegol E5D or E7D. The primary endpoint was annualized bleeding rate (ABR), and secondary endpoints included measures of joint health and safety. Safety analyses were primarily performed on treatment-emergent adverse events (TEAEs) in the safety analysis set population. Effectiveness analyses were primarily performed on the full analysis set (FAS). Data were captured from patient diaries and physician records, and ethical approval was obtained for all sites. Results: At data cut-off (31 August 2021), a total of 162 patients were enrolled in the study. In this subgroup analysis, 21 patients in the FAS received prophylactic treatment E5D (n=14) or E7D (n=7). The majority of patients had severe HA (n=12/14, 85.7% E5D; n=5/7, 71.4% E7D). Prior to initial visit, all patients received FVIII replacement therapy; some of these patients received prior damoctocog alfa pegol prophylactic treatment (n=7/14, 50.0% E5D; n=5/7, 71.4% E7D). The proportion of patients with no affected joints increased over time in both E5D and E7D subgroups (Figure 1). In the E5D subgroup at follow-up 1 (n=10), 40.0% of patients had no affected joints. In the E7D subgroup, all patients reported no affected joints at the first follow-up (n=5). Median (mean, SD) total ABR was 0.0 (1.0, 1.6) for the E5D subgroup and 0.0 (0.8, 1.5) for the E7D subgroup. The median (mean, SD) difference in ABR between observation period and prior to initiation of damoctocog alfa pegol in the E5D and E7D subgroups is reported in Table 1. No development of FVIII inhibitors, TEAEs, or deaths were reported. Conclusions: Damoctocog alfa pegol continues to show a favorable effectiveness and safety profile in PTPs with mild, moderate, or severe hemophilia in a real-world clinical setting with extended prophylactic dosing intervals. Improvements in joint health and ABR were demonstrated with both E5D and E7D prophylaxis regimens. The option of extended dosing intervals allows for further PK-guided treatment individualization for selected patients, based on bleeding phenotype and lifestyle, without compromising treatment efficacy. References Bayer. Damoctocog alfa pegol (Jivi®). Prescribing Information. Last updated August 2018. Available at: https://www.fda.gov. Accessed: July 2022. Reding MT, Pabinger I, Holme PA, et al. Haemophilia. 2021;27:e347-e356. Reding M, Alvarez Román M, Sanabria M, et al. [abstract presented at ISTH 2021]. Res Pract Thromb Haemost. 2021;5(Suppl 2). Reding M, Alvarez Román M, Sanabria M, et al. [abstract presented at ISTH 2022]. https://abstracts.isth.org/abstract/annualised-bleeding-rate-and-joint-health-second-interim-analysis-of-the-real-world-hem-powr-study-evaluating-the-effectiveness-of-damoctocog-alfa-pegol-in-patients-with-haemophilia-a/. Accessed July 19, 2022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RECLASSIFICATION OF PATIENTS WITH HEMOPHILIA A BY MOLECULAR DIAGNOSIS

The state of Minas Gerais has the third largest population of hemophilia A (HA) patients in Brazil. Fundação Hemominas is the treatment center of reference in the state for clinical and laboratory care of HA patients. Patients are classified according to residual plasma FVIII activity (FVIII:C): Patients with FVIII:C 5%-40% are classified as mild HA; FVIII:C of 1%-5% are classified as moderate HA; and patients with FVIII:C <1% are classified as severe HA. Patients with severe HA often have inversions of introns 1 and 22 in the FVIII gene. The aim of this study was to diagnose inversions of introns 1 and 22 patients with severe and moderate HA. For this purpose, peripheral blood samples were collected from 39 male patients, median (MED) age was 31 years (IQR 19 -42 years), classified as severe (27 patients) or moderate (12 patients) with FVIII:C dosage <3%. After collection, samples were processed for genomic DNA extraction. First, patients were genotyped for intron 22 inversion by inverse PCR. Patients who were negative for intron 22 inversion were genotyped for intron 1 inversion. Samples negative for both inversions will be full-length NGS sequencing. Among 39 patients, 21 (54%) were diagnosed with intron 22 inversion and one (2%) with intron 1 inversion. In addition, among 12 patients previously diagnosed with moderate HA, seven (58%) patients were reclassified as severe HA because they presented intron 22 inversion. The molecular diagnosis proved to be important for the correct classification of the severity of HA patients. Due to the diagnosis normally based only on residual activity of plasmatic FVIII, the disease severity classification may be incorrect. It is believed that the high variability of coagulometric techniques and the treatment of patients prior to laboratory diagnosis may affect the correct classification of HA patient severity. This is an ongoing study and the number of participants needs to be increased in order to draw conclusions. We thank all participants, Fapemig, Hemominas, and the CGSH of the Ministry of Health.