Previously Untreated Patients Research Articles

Real-world long-term safety and effectiveness of turoctocog alfa in the treatment of haemophilia A in Japan: results from a multicentre, non-interventional, post-marketing study

ABSTRACT Objectives To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan. Methods This multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period. Results The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69–10.38). The mean (SD) total consumption of turoctocog alfa (n = 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis. Discussion The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens. Conclusion Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.

A post hoc analysis of previously untreated patients with severe hemophilia A who developed inhibitors in the PUPs A-LONG trial

AbstractInhibitor development is a major therapeutic complication for people with hemophilia. The phase 3 PUPs A-LONG study evaluated the safety and efficacy of efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, herein referred to as rFVIIIFc) in previously untreated patients (PUPs) with severe hemophilia A. Male PUPs <6 years old were enrolled and received rFVIIIFc; inhibitor development was the primary end point. Post hoc analyses, including patient treatment regimen patterns and timing of inhibitor development, descriptive and Kaplan-Meier analyses of time to first inhibitor-positive test by treatment regimen and by titer, and consumption, were performed to describe patients who developed inhibitors during PUPs A-LONG. We investigated patient characteristics (eg, demographics and genotype) and nongenetic risk factors (eg, intense factor exposure and central venous access device [CVAD] placement) that may predict inhibitor development and characteristics of inhibitor development (low-titer vs high-titer inhibitor). Baseline characteristics were similarly distributed for age, race, and ethnicity across both patients who were inhibitor-positive and those who were inhibitor-negative (all P > .05). High-risk F8 variants were associated with development of high-titer inhibitors (P = .028). High-titer inhibitor development was often preceded by the presence of a low-titer inhibitor. Patients whose low-titer inhibitor progressed to a high-titer inhibitor received a higher mean dose per infusion (98.4 IU/kg, n = 5) compared with those whose low-titer inhibitor resolved spontaneously (59.2 IU/kg, n = 7; P = .033) or persisted (45.0 IU/kg, n = 5; P = .047). There was no association between CVAD placement surgery and inhibitor development. Post hoc analyses suggest that F8 genotype and dose of factor are as important as inhibitor risk factors and require further investigation. This study was registered at ClinicalTrials.gov as #NCT02234323.

Safety and Efficacy of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Untreated Patients with Hemophilia B.

Introduction Recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) has been shown to be an effective, well-tolerated treatment for patients with severe hemophilia B who had previously received factor replacement therapy. This study investigated the safety and efficacy of rIX-FP in previously untreated patients (PUPs). Methods Patients with moderately severe/severe hemophilia B (≤2% FIX) previously untreated with FIX replacement products received rIX-FP (25-75 IU/kg) prophylaxis weekly or on-demand treatment over ≥50 exposure days (EDs). Primary outcomes were the number of patients who developed FIX inhibitors and mean incremental recovery (IR) following a 50 IU/kg dose of rIX-FP. Secondary outcomes included incidence of adverse events (AEs) and annualized bleeding rates (ABRs). Results In total, 12 PUPs with a median age of 0 years (range, 0-11 years) were treated with rIX-FP for a median of 50 EDs (6/12 prophylaxis; 6/12 on-demand then prophylaxis). Overall, 11/12 patients did not develop FIX inhibitors; one 11-year-old patient developed an inhibitor against FIX after 8 EDs and was ultimately withdrawn. Mean (standard deviation) IR was 1.2 (0.4, n = 8) (IU/dL)/(IU/kg). Of the 137 treatment-emergent AEs recorded, five were attributed to rIX-FP. On the prophylaxis regimen, median ABR was 1.0 (range, 0-3.9, n = 12). No thromboembolic events or deaths occurred during the study. Conclusion This study provides data to support the safety and efficacy of rIX-FP in PUPs requiring on-demand or prophylactic treatment for moderately severe/severe hemophilia B, consistent with results in previously treated patients. Overall, 1/12 patients developed an inhibitor against FIX.

Transcriptomic Profiling to Understand Inhibitor Development in Previously Untreated Patients with Severe Hemophilia a

Background: When starting treatment with factor VIII (FVIII) concentrate in individuals with severe hemophilia A, minimizing the risk of FVIII inhibitor development is an important concern for clinicians, patients and their families. Despite increased understanding of some of the genetic and environmental risk factors for inhibitor formation from epidemiological studies, identification of previously untreated patients (PUPs) at risk of developing inhibitors remains a challenge. Prediction of inhibitor development may help optimize care in PUPs with hemophilia A. RNA sequencing (RNA-Seq) with next-generation sequencing (NGS) could be used to investigate the underlying mechanisms of inhibitor development. Aims: Toevaluate peripheral blood transcriptomic profiles prior to and during early FVIII treatment in severe hemophilia A patients who did or did not develop inhibitors to simoctocog alfain the prospective NuProtect study. Methods: The NuProtect study (NCT01712438; EudraCT 2012-002554-23) was a multicenter, multinational, open-label, non-controlled, phase III study that enrolled male PUPs with severe hemophilia A (FVIII:C &amp;lt;1%) of any age and ethnicity. Patients received simoctocog alfa for prophylaxis or on-demand treatment, as well as for surgical prophylaxis. RNA-Seq was performed on blood samples collected from baseline and every 3-4 exposure days (ED) up to 20 EDs or until inhibitor development to assess messenger RNA (mRNA) expression profiles. Bioinformatics analyses were performed for the following timepoints: baseline, early treatment and a later timepoint on treatment. Principal component analysis (PCA) was performed to identify differences in global mRNA expression profiles between inhibitor and non-inhibitor patients. Gene ontology (GO) analyses were performed to detect differences in GO clusters between inhibitor and non-inhibitor patients. Results: Within this first analysis of the full dataset, transcriptomic profiles from 78 of 108 severe hemophilia A PUPs were analyzed (inhibitors n=22, non-inhibitors n=56). Median (range) age at ED1 was 13 (0.5-146) months; 44.9% of patients had the intron 22 inversion F8 gene mutation. Although the PCA indicated no strong global signal for differential expression profiles between non-inhibitor and inhibitor patients, GO analyses demonstrated differences between these patient groups. Inhibitor patients demonstrated increased gene expression of metabolic processes (GO:0008152) and cellular processes (GO:0009987) at baseline. Upregulation of immune system processes (GO:0002376) was seen in inhibitor patients at the early timepoint compared with non-inhibitor patients. Expression of ribosomal proteins, including RPL17 and RPS8 were significantly upregulated at baseline in inhibitor patients (p&amp;lt;0.05). Inhibitor patients further demonstrated upregulation of proteins involved in adaptive immune responses: IGHV1-69-2 at all timepoints (p&amp;lt;0.01) and IGHV2-70D at baseline and the early timepoint (p&amp;lt;0.01) compared with non-inhibitor patients. Upregulation of the B-cell related factors DPP4 at baseline and the early timepoint (p&amp;lt;0.05) and CD20 at the late timepoint (p&amp;lt;0.05) was observed in inhibitor patients compared with non-inhibitor patients. Conclusion: Differential transcriptomic profiles were seen in severe hemophilia A patients who developed inhibitors compared with those who do not, even before commencing FVIII treatment. Inhibitor patients demonstrated alterations in ribosomal protein expression that could disrupt protein synthesis efficiency, protein folding and quality control processes, and trigger cellular stress responses. Inhibitor patients also showed an upregulation of B-cell mediated factors involved in adaptive immune mechanisms. Additional analyses are ongoing to evaluate dynamic changes in gene expression during commencement of FVIII replacement to further identify patients at risk of inhibitor development.

Post-Immune Tolerance Induction Prophylactic FVIII Infusions May Not be Necessary for Tolerized Hemophilia a Patients on Emicizumab

Background: Hemophilia A is a hereditary bleeding disorder characterized by low factor VIII (FVIII) activity. Patients with severe bleeding phenotypes are at risk for significant bleeding-related morbidity and mortality including the development of hemophilic arthropathy. In recent years, prophylaxis with emicizumab, a bispecific monoclonal antibody, has supplanted prophylactic FVIII infusions due to its ease of self-administration, long half-life, and low annual bleeding rate (ABR), independent of tolerization status to alloantibodies against FVIII (inhibitors). However, it is unclear if emicizumab FVIII-mimic activity is sufficient to achieve hemostasis in moderate-severe bleeds, and therefore, FVIII replacement may still be necessary. Despite its well-established benefits, the use of emicizumab in previously untreated patients (PUPs), and patients with under 20 exposures to FVIII is still not well understood due to a lack of long-term experience and understanding of its impact on the pathophysiology of FVIII inhibitors. Further investigation is also needed regarding the risk of inhibitor recurrence in patients with previous inhibitors and the concomitant use of emicizumab. At our institution, patients on emicizumab with a history of inhibitors do not continue post-immune tolerance induction prophylactic FVIII infusions. We also initiate emicizumab before 20 exposures to FVIII, and sometimes before immune tolerance induction (ITI). We explored our patient population to understand inhibitor incidence and recurrence amidst emicizumab prophylaxis. Methods: We performed a single center retrospective analysis of patients served by the Hemophilia Center of Western Pennsylvania. We identified patients with Hemophilia A on emicizumab prophylaxis. Relevant data was collected including demographics, inhibitor status at time of transition to emicizumab and in the available follow-up period, bleeding events after transition, and number of FVIII exposures before and after transition. Inhibitor recurrence was defined as laboratory evidence of inhibitor using chromogenic Bethesda assay and/or unexplained breakthrough bleeding events despite on-demand FVIII infusions. Results: Data was reviewed for 36 patients on emicizumab prophylaxis. Three patients were lost to follow-up. Median age was 15.3 years (range 1.2 - 82). Median follow-up time on emicizumab was 3.5 years (range 0.5 - 5). Two patients had &amp;lt; 20 FVIII exposures prior to emicizumab, and one of those had an inhibitor before emicizumab. In total, 15 patients (45%) were diagnosed with an inhibitor prior to emicizumab. Of these, 8 patients (53%) were tolerized prior to emicizumab, and 7 patients (47%) were not tolerized prior to emicizumab. Median peak inhibitor titer was 4.2 Bethesda units (range 0.7 - 281 Bethesda units). After transition to emicizumab, no tolerized patients for which inhibitor status was tested during the follow-up period had inhibitor recurrence, and 1 non-tolerized patient's inhibitor became undetectable after 4 years of emicizumab therapy (the same patient who had developed an inhibitor with &amp;lt; 20 FVIII exposures prior to emicizumab). Mean ABR was 0.33 events/year for tolerized patients (median 0, range 0 - 3); 0.17 events/year for non-tolerized patients (median 0, range 0 - 1); and 0.60 events/year for patients with no history of inhibitor (median 0, range 0 - 4). Mean number of FVIII exposures per year was 0.09 for tolerized patients (median 0, range 0 - 1); 0.07 for non-tolerized patients (median 0, range 0 - 1); and 1.2 for patients with no history of inhibitor (median 0, range 0 - 20). Conclusion: In our small cohort, no patient who was tolerized prior to emicizumab had recurrence of clinical or laboratory evidence of inhibitor while on emicizumab therapy, despite infrequent exposure to FVIII infusion. We did not have enough power to determine whether patients with &amp;lt; 20 FVIII exposures before emicizumab developed inhibitors, though one such patient had inhibitor resolution on emicizumab without ITI. Consistent with other works, overall ABRs in all patients on emicizumab therapy were low. These findings add to other studies on the safety of emicizumab and its impact on the natural history of FVIII inhibitors. Our study also suggests that continuing post-ITI prophylactic FVIII infusions in tolerized patients on emicizumab may not be necessary. Larger-scale studies are required to substantiate our findings.

Inhibitor development according to concentrate in severe hemophilia: reporting on 1392 Previously Untreated Patients from Europe and Canada

BackgroundClotting factor concentrates have been the mainstay of severe hemophilia treatment over the last 50 years. Differences in risk of neutralizing antibody (inhibitor) formation according to concentrate used remain clinically relevant. ObjectivesTo assess inhibitor development according to type of clotting factor concentrate in previously untreated patients (PUPs) with severe hemophilia A and B. MethodsThe European Haemophilia Safety Surveillance (EUHASS) and Canadian Bleeding Disorders Registry (CBDR) have been monitoring adverse events overall and according to concentrate for 11 and 8 years, respectively. Inhibitors were reported quarterly, and PUPs completed 50 exposure days without inhibitor development annually. Cumulative inhibitor incidences and 95% confidence intervals (CIs) were compared without adjustment for other risk factors. ResultsFifty-six European and 23 Canadian centers reported inhibitor development in 312 of 1219 (26%; CI, 23%-28%) PUPs with severe hemophilia A and 14 of 173 (8%; CI, 5%-13%) PUPs with severe hemophilia B. Inhibitor development was lower on plasma-derived factor (F)VIII (pdFVIII, 20%; CI, 14%-26%) than on standard half-life recombinant FVIII (SHL-rFVIII, 27%; CI, 24%-30% and odds ratio, 0.67; CI, 0.45%-0.98%; P = .04). Extended half-life recombinant FVIII (EHL-rFVIII, 22%; CI, 12%-36%) showed an intermediate inhibitor rate, while inhibitor rates for Advate (26%; CI, 22%-31%) and Kogenate/Helixate (30%; CI, 24%-36%) overlapped. For other SHL-rFVIII concentrates, inhibitor rates varied from 3% to 43%. Inhibitor development was similar for pdFIX (11%; CI, 3%-25%), SHL-rFIX (8%; CI, 3%-15%), and EHL-rFIX (7%; CI, 1%-22%). ConclusionWhile confirming expected rates of inhibitors in PUPs, inhibitor development was lower in pdFVIII than in SHL-rFVIII. Preliminary data suggest variation in inhibitor development among different SHL-rFVIII and EHL-rFVIII concentrates.

The prophylaxis of severe hemophilia A with inhibitors in children in the Republic of Belarus: a 12-year experience

The development of inhibitory antibodies against FVIII is the most serious complication associated with the use of FVIII concentrates in hemophilia A patients. There is a need for more research on measures that could reduce the risk of inhibitor formation in previously untreated patients (PUPs) with severe hemophilia A. The purpose of this study was to determine the effectiveness of the prevention of clotting inhibitor development in PUPs (or minimally treated patients) with severe hemophilia A by administering plasma-derived factor VIII concentrate (pdFVIII) at a dose of 25 IU/kg once a week for a year. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). Between 2010 and 2022, 56 boys were newly diagnosed with severe hemophilia A. Twenty-one of them received pdFVIII as on-demand treatment to stop bleeding (Group 1). Thirty-five boys received pdFVIII at a dose of 25 IU/kg body weight once a week during the first 50 weeks of treatment for the prevention of inhibitor development (Group 2). The administration of pdFVIII at a dose of 25 IU/kg once a week in the PUPs (or minimally treated patients) contributed to a decrease in the cumulative incidence of inhibitors to 15.9 ± 7.7% (4 out of the 35 patients who had been treated prophylactically) compared with 43.7 ± 11.8% (8 out of the 21 patients who had received hemostatic therapy to stop bleeding) (log-rank test, p = 0.041). Thus, the administration of pdFVIII concentrate at a dose of 25 IU/kg once a week for the first 50 weeks of treatment lead to a decrease (p = 0.009) in the cumulative incidence of inhibitors against the administered coagulation factor VIII to 15.9 ± 7.7%.

PB0648 Mitigating the Risk of Bleeds and the Risk for Inhibitor Formation when Treating Previously Untreated Patients (PUPs) with Severe Haemophilia A - A Single-Centre Approach

PB0648 Mitigating the Risk of Bleeds and the Risk for Inhibitor Formation when Treating Previously Untreated Patients (PUPs) with Severe Haemophilia A - A Single-Centre Approach

Risk factors for coagulation inhibitor development in children with severe hemophilia A

Aim of the study: to examine the role of potential risk factors in inhibitor development in previously untreated patients (PUPs) (or minimally treated patients) with severe hemophilia A. The study was approved by the Independent Ethics Committee and the Scientific Council of the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus). The study included 89 boys who underwent regular follow-up for severe hemophilia A at the Belarusian Research Center for Pediatric Oncology, Hematology and Immunology (the Republic of Belarus) from 1998 to 2022. The median age (10th–90th percentile) at diagnosis of hemophilia was 8.0 (1.0–21.0) months, the baseline factor VIII activity was 0.7% (0.4–0.95%). Age at first exposure to factor VIII concentrate was 11.0 (1.0–31.0) months. Out of 89 patients, 23 children had severe hemophilia A with inhibitors. The cumulative incidence of inhibitors in the whole group of PUPs was 31.0 ± 5.6%. The cumulative incidence of hemophilia A with inhibitors was higher in the patients with null mutations (37.0 ± 6.9%) than in the patients with non-null mutations (6.5 ± 6.0%) (the log-rank test, p = 0.041). The use of plasma-derived FVIII concentrate (approved for use in neonates and for prophylaxis) from one manufacturer was associated (c2 = 8.53; p = 0.004) with a lower incidence of factor VIII inhibitors (up to 21.3 ± 8.5%) compared with the incidence in the group of patients treated with FVIII concentrates from different manufacturers (45.2 ± 7.8%). Age (&gt; 1 year old or &lt; 1 year old) at first exposure to FVIII had no effect on the formation of inhibitors (the log-rank test, p = 0.746). Such factors as age at diagnosis of hemophilia (odds ratio (OR) 0.99; 95% confidence interval (CI) 0.93–1.024; p = 0.991) and baseline factor VIII activity (OR 0.99; 95% CI 0.8–1.06; p = 0.09) were not associated with inhibitor development. The first measurements of activated partial thromboplastin time (APTT) ratio (patient APTT value over the APTT reference value) (OR 1.89; 95% CI 0.72–5.09; p = 0.21) and FVIII recovery in vivo (OR 0.74; 95% CI 0.27–2.01; p = 0.55) were not associated with inhibitor development either. We have confirmed that one of the main risk factors for FVIII inhibitor development is F8 gene mutations. The incidence of inhibitors among the patients who received plasma-derived FVIII concentrates (recommended for use in PUPs in the neonatal period) from one manufacturer was lower than among those who received FVIII from different manufacturers.

Immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients with severe hemophilia A: interim results from a phase 3, prospective, multicenter, open-label study

ABSTRACT Aim To determine the immunogenicity, safety, and efficacy of rurioctocog alfa pegol in previously untreated patients (PUPs) with severe hemophilia A (HA). Methods This prospective, phase 3 study (NCT02615691) was conducted in PUPs, or patients with ≤2 exposure days (EDs) prior to screening, aged <6 years with severe HA. The primary endpoint was incidence of factor VIII (FVIII) inhibitor development. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing FVIII inhibitors or had developed a confirmed inhibitor at any time. Results Of the enrolled patients, 59/80 (73.8%) received ≥1 dose of rurioctocog alfa pegol; 54 received prophylaxis, and 35 on-demand treatment. Incidence of inhibitor development was 0.19 (10/52). Total annualized bleeding rate (95% CIs) was 3.2 (2.0–5.0) for patients receiving prophylaxis and 3.2 (1.6–6.3) for on-demand treatment. Hemostatic efficacy of most bleedings was rated as ‘excellent’ or ‘good’ after 24 hours (122/131 [93.1%]) and at resolution (161/170 [94.7%]). Five patients received ≥1 dose of rurioctocog alfa pegol for immune tolerance induction (ITI) and 1 patient was defined as having ITI success. Thirteen patients experienced 14 treatment-related adverse events, including 10 cases of FVIII inhibitor development. Conclusion This is the first prospective study of rurioctocog alfa pegol for the treatment of PUPs with severe HA. Trial Registration This trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT02615691).

The immunogenicity, safety, and efficacy of N8-GP in previously untreated patients with severe hemophilia A: pathfinder6 end-of-trial results

BackgroundThe pathfinder6 (NCT02137850) international phase 3 trial examined immunogenicity, safety, and efficacy of the extended half-life factor VIII (FVIII) replacement product N8-GP (turoctocog alfa pegol; Esperoct) in previously untreated patients (PUPs) with hemophilia A. ObjectivesWe present end-of trial results for extended PUP N8-GP treatment for up to a median (range) 2.5 (0.0; 7.4) years. Patients/MethodsLonger-term N8-GP treatment in PUPs with hemophilia A was examined. The prophylaxis regimen was ∼60 IU/kg N8-GP i.v. twice weekly, or every 3 or 7 days. The primary endpoint was the incidence of FVIII inhibitors. ResultsOverall, 81 patients received N8-GP and were included in this analysis. The inhibitor incidence was 30.0% (15.7% high-titer [>5 BU]) for the extension phase. Patients had a median (range) 2.9 (0.1; 7.2) years of prophylaxis following the pre-prophylaxis period. During prophylaxis, the median annualized bleeding rate (ABR) (interquartile range) was 1.4 (0.6; 3.5), 13% of patients experienced no bleeding episodes, and 55.1% of patients experienced no spontaneous bleeds. The proportion of patients without any spontaneous bleeding episodes increased after the first year of prophylaxis. The hemostatic success rate in the treatment of bleeding episodes was 87.6%. No additional safety concerns were observed in patients with previously reported observation of temporarily decreased incremental recovery (IR). ConclusionLong-term end-of-trial PUP N8-GP prophylaxis data indicate that PUPs respond well to long-term N8-GP treatment. The inhibitor incidence was consistent with previous results. Median ABR during prophylaxis was 1.4. There were no lasting clinical impacts or safety concerns for patients with an observation of temporarily decreased IR.

Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. To report the efficacy and safety results from the NuProtect study. PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

Design of a Real-World Observational Study in Previously Untreated and Minimally Treated Hemophilia A Patients: Protect-NOW.

Background The efficacy, safety, and immunogenicity of each of Octapharma's factor VIII (FVIII) products, Nuwiq, octanate, and wilate, have been investigated in previously untreated patients (PUPs) with severe hemophilia A in prospective clinical trials. The aim of the Protect-NOW study is to evaluate the effectiveness, safety, and utilization patterns of Nuwiq, octanate, and wilate in PUPs and minimally treated patients (MTPs; <5 exposure days [EDs] to FVIII concentrates or other blood products containing FVIII) with severe hemophilia A in a real-world setting. Real-world data provide valuable information that complement data obtained from interventional clinical trials. Methods Protect-NOW (ClinicalTrials.gov identifier: NCT03695978; ISRCTN identifier: 11492145) is a real-world study in PUPs and MTPs treated with either the human cell line-derived recombinant FVIII Nuwiq (simoctocog alfa) or a plasma-derived FVIII concentrate containing von Willebrand factor (octanate or wilate). It is a prospective and (partly) retrospective, observational, international, noncontrolled, noninterventional study. A total of 140 PUPs and MTPs with severe hemophilia A will be enrolled across around 50 specialized centers worldwide and followed for either 100 EDs or a maximum period of 3 years from ED1. The primary objectives are to assess effectiveness in the prevention and treatment of bleeding episodes and overall safety, including inhibitor development. The secondary objectives are to assess utilization patterns (including dosage and frequency of administration) and the effectiveness in surgical prophylaxis. Conclusions The Protect-NOW study will provide information on the treatment of PUPs and MTPs in routine clinical practice, which will help guide clinical decision making for treating these patients in the future.

U.S. Cohort Study of Previously Untreated Patients with Congenital Hemophilia (ATHN 8: PUPs Study): Inhibitor Development and Treatment Characteristics

Background: Persons with hemophilia (PWH) are at risk of developing neutralizing inhibitors to factor product. While some risk factors for inhibitor development are known, mechanisms to delay or prevent this complication are less well understood. American Thrombosis and Hemostasis Network (ATHN) 8: U.S. Cohort Study of Previously Untreated Patients (PUPs) with Congenital Hemophilia (NCT03818529) is a longitudinal cohort study of PUPs with moderate or severe hemophilia A (HA) or B (HB) born between 1/2010 and 12/2021 and enrolled from participating ATHN-affiliated hemophilia treatment centers (HTCs). Through this study we sought to understand variables that contribute to inhibitor development. Methods: At each HTC, data were entered for participants until 50 clotting factor exposure days (EDs), development of a confirmed neutralizing inhibitor, or study closure. The primary outcome was inhibitor development defined as a Bethesda Unit (BU) titer of >0.6 for HA or >0.3 for HB and a change in treatment. Secondary outcomes included diagnosis and treatment characteristics. Summary statistics were performed. For participants who met study endpoints at the time of enrollment, logistic regression analysis was utilized to evaluate birth cohort, race, hemophilia severity, genetic variant (for F8 gene only, classified as large structural changes >50 bp, other, and not sequenced), prophylaxis, and 5 or more consecutive EDs as risk factors for inhibitor development. Results: The study enrolled 234 eligible male participants including 135 who had met study endpoints at the time of enrollment; 94 with 50 EDs and 41 with inhibitor. A total of 128 (128/234 = 55%) were White, non-Hispanic. Of 114 HA participants who met a study endpoint prior to enrollment, 38 (38/114 = 33%) developed an inhibitor (3 moderate, 35 severe). The median EDs prior to inhibitor development was 14 (min 1, max 75). Of 21 HB participants who met a study endpoint prior to enrollment, 3 (3/21 = 14%) developed an inhibitor, all with severe disease. The median EDs to inhibitor development was 9 (min 8, max 10). Of the 234 eligible participants, 135 (135/234 = 58%) were on prophylactic treatment at any point. Of these, 33 (33/135 = 24%) received extended half-life (EHL) factor products (HA 20/114 = 17.5%; HB 13/21= 62%), while 14 (14/114 = 12%) with HA were receiving emicizumab. Over the course of the study, the rate of usage of emicizumab rose from 2% to 12% in participants with HA. Seventeen (17/39 = 44%) with HA were on prophylaxis at the time of inhibitor development, including 11 (11/39 = 28%) on standard half-life clotting factor, 1 (3%) on EHL clotting factor, and 0 on emicizumab. One participant with HB was on prophylaxis at the time of inhibitor development: none on standard half-life clotting factor, 1 (1/3 = 33%) on EHL clotting factor. Those who were on prophylaxis had decreased risk of confirmed inhibitor compared to those who were not (Odds ratio 0.24; 95% CI 0.09, 0.67). 89 participants with HA had F8 genetic testing completed, including 10 (11%) with large structural deletions. Large structural deletions were associated with higher inhibitor risk compared to other mutations in PUPs with HA at the time of inhibitor development (Odds Ratio = 5.32 vs. those with other mutations, 95% CI 1.27, 22.25). Race, ethnicity, birth cohort, and 5 or more consecutive EDs were not associated with inhibitor development. Conclusion: In ATHN 8, inhibitor rates for PUPs with HA were consistent with published data and within the typical ED range. Prophylaxis appears to decrease the risk of inhibitor development. As expected, inhibitor development was associated with large structural deletions compared to other variant types in HA. Inhibitor occurrence was not associated with other traditional risk factors. For HB, the inhibitor rate was higher than most previous reports, which may be due to the small number of participants. For PUPs with HA, emicizumab prophylaxis increased over the course of the study period. These results support the use of prophylaxis as a prevention strategy for inhibitor development. Longitudinal follow-up is needed to determine if new treatment products (EHL clotting factor and emicizumab) are associated with changes in inhibitor rates or age at inhibitor development. Although ATHN 8 was closed to enrollment, PUPs will continue to be enrolled and followed in ATHN Transcends (NCT04398628), a natural history study including PUPs with hemophilia.

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

Incidence of Inhibitors in Previously Untreated Patients with Severe Hemophilia a Treated with Plasma-Derived Vs. Recombinant Factor VIII Concentrates: A Systematic Review and Meta-Analyses

Introduction: The most important treatment complication of hemophilia A is the development of neutralizing antibodies anti-factor VIII (inhibitors). Among the non-genetic risk factors for inhibitors development, the influence of the type of factor concentrate used in replacement therapy remains controversial. Objective: The aim of this study was to systematically review the incidence of inhibitor development after treatment with recombinant factor FVIII (rFVIII) compared with plasma factor FVIII (pdFVIII) in previously untreated patients (PUPs) with severe hemophilia A. Methods: A computer-assisted search of MEDLINE, Cochrane Library, EMBASE, Scopus, Google Scholar and Web of Science, without language restriction, between January 2010 and May 2022, was conducted using different combinations keywords. Other publications were selected from presentations from the largest conferences in the area, to identify relevant studies not detected in the electronic search. Additional studies were identified by contacting experienced researchers in the field and searching the reference list of primary studies. The articles were analyzed by two independent reviewers using pre-established eligibility criteria and in case of disagreement, a third independent reviewer was responsible for the final decision. To avoid double counting of the same cohort of patients, study periods were observed, and patients in duplicates were excluded. Data extraction form was made using the RedCap Platform. If some study data were missing or incomplete, an email was sent to the corresponding author to obtain the information. Quality assessment was performed on all included studies using The Newcastle-Ottawa Scale for Observational Cohort and Case Control Studies (NOS) and The Cochrane RoB 2.0 scale. Results: Of the 974 potentially relevant publications initially selected, 34 were included in the final analysis, published between January 2010 to May 2022. Data from 4,244 patients enrolled in these studies were included in this analysis. Of these, 1,047 received pdFVIII, and 3,324 received rFVIII. The total number of patients who developed inhibitors was 1,136, of which 204 (19.5%) were treated with pdFVIII and 929 (28.8%) with rFVIII. High-titer inhibitors were found in 730/4,271 (17.1%) patients, 144/1,047 (13.8%) for pdFVIII and 585/3,224 (18.1%) for rFVIII. The pooled analysis of all studies showed inhibitor incidence rate of 17% for pdFVIII vs. 28% for rFVIII. Regarding high-titer inhibitors, the pooled incidence rate was 11% for pdFVIII studies compared to 17% for rFVIII (figure 1). Analyzing the different generations of rFVIII, it was observed the inhibitor incidence rate of 19% for first-generation rFVIII, 31% for the second-generation, 26% for third-generation and 27% for fourth-generation. Considering only the pooled incidence rate of high-titer inhibitors, it was observed 15%, 23%, 15% and 16 %, respectively. The inhibitor incidence rate in patients who received extended half-life (EHL) rFVIII was 28%, with 14% of high-titer inhibitor. Comparing pdFVIII concentrates to standard rFVIII, there was a statistically significant difference (p = 0.004). Regarding the two EHL-rFVIII concentrates with data available in the literature on PUPs (rFVIII-Fc [Elocta®] and N8-PEG [Esperoct®]) it was demonstrated also a statistical difference in inhibitor development compared to pdFVIII (p = 0.003). However, when compared inhibitor incidence rate of third-generation rFVIII and EHL-rFVIII, no statistical difference was observed. Nevertheless, the incidence rate of high-titer inhibitors among patients using pdFVIII and rFVIII, was statistically different only with second-generation rFVIII concentrates (p = 0.001). Conclusions: In our systematic review and meta-analysis, which included 34 studies, an increase in the incidence of inhibitors was demonstrated in patients who used rFVIII when compared to pdFVIII. However, when analyzing only high-titer inhibitors, there was statistical difference only with second-generation rFVIII, which are not commonly used nowadays. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Immunogenicity, Safety and Efficacy of N8-GP in Previously Untreated Patients (PUPs) with Severe Hemophilia A: pathfinder6 End-of-Trial Results

The Immunogenicity, Safety and Efficacy of N8-GP in Previously Untreated Patients (PUPs) with Severe Hemophilia A: pathfinder6 End-of-Trial Results

Inhibitors: Diagnostic challenges, unknowns of inhibitor development, treatment of bleeding and surgery, and insights into diagnosis and treatment in China.

Factor (F) VIII inhibitors develop in around 30% of previously untreated patients (PUPs) with severe haemophilia, to a lesser extend in moderate and mild haemophilia A and in up to 10% in severe haemophilia B. Diagnostic challenges and questions remain including access to high quality testing, the role for functional inhibitor testing and binding antibody testing, and the adaptations needed in the presence of non-factor replacement therapy. Despite significant gains in knowledge there are still many unanswered questions underlying the immunologic mechanisms of inhibitor development and tolerance. Therapeutic options include eradication of inhibitors using immune tolerance induction therapy (ITI), prophylaxis with bypassing agents (i.e., recombinant activated factor VII /rFVIIa or activated prothrombin complex concentrate/aPCC) or non-factor replacement therapies (e.g., emicizumab) and treatment of bleeds or coverage of surgeries/invasive procedure. Recently a haemophilia centre capacity building program was launched in China to further develop the infrastructure and support needed to improve the diagnosis of haemophilia, detection of inhibitors, and continue to improve the care of patients with haemophilia and inhibitors.

First study of extended half-life rFVIIIFc in previously untreated patients with hemophilia A: PUPs A-LONG final results

AbstractPUPs A-LONG evaluated the safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously untreated patients (PUPs) with hemophilia A. This open-label, phase 3 study enrolled male PUPs (<6 years) with severe hemophilia A to receive rFVIIIFc. The primary endpoint was the occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR). Of 103 subjects receiving ≥1 dose of rFVIIIFc, 80 (78%) were aged <1 year at the study start, 20 (19%) had a family history of inhibitors, and 82 (80%) had high-risk F8 mutations. Twenty subjects began on prophylaxis, while 81 began an on-demand regimen (69 later switched to prophylaxis). Eighty-seven (81%) subjects completed the study. Inhibitor incidence was 31.1% (95% confidence interval [CI], 21.8% to 41.7%) in subjects with ≥10 exposure days (or inhibitor); high-titer inhibitor incidence was 15.6% (95% CI, 8.8% to 24.7%). The median (range) time to high-titer inhibitor development was 9 (4-14) exposure days. Twenty-eight (27%) subjects experienced 32 rFVIIIFc treatment-related adverse events; most were inhibitor development. There was 1 nontreatment-related death due to intracranial hemorrhage (onset before the first rFVIIIFc dose). The overall median (interquartile range [IQR]) ABR was 1.49 (0.00-4.40) for subjects on variable prophylaxis dosing regimens. In this study of rFVIIIFc in pediatric PUPs with severe hemophilia A, overall inhibitor development was within the expected range, although high-titer inhibitor development was on the low end of the range reported in the literature. rFVIIIFc was well-tolerated and effective for prophylaxis and treatment of bleeds. This trial is registered at www.clinicaltrials.gov (NCT02234323).

Perioperative bevacizumab in the treatment of colorectal cancer in patients with liver metastases

Introduction. Patients with colorectal cancer with metastases in the liver parenchyma may benefit from perioperative chemotherapy with biological agents and operative liver resection. Material and Methods. This prospective, multicenter, non-interventional study included 191 previously untreated patients with metastatic colorectal cancer and potentially resectable or initially unresectable liver metastases who received bevacizumab plus chemotherapy. The safety profile, as well as progression-free-survival, response rate and conversion rate of initially unresectable metastases to resectable were assessed. Results. A total of 40 adverse events were reported in 29/191 patients (15.2%), of which 31 were serious adverse events. Among the serious adverse events, 14 were related to the use of bevacizumab therapy, of which 4 were fatal due to serious adverse events, but only one could be related to bevacizumab therapy. The median progression-free period was 9 months (1 - 28). A high rate of response to the applied therapy, 34.5% and 49%, was recorded in both groups of patients: with initially unresectable and potentially resectable metastases in the liver parenchyma. A significant part of patients with metastatic colorectal cancer and metastases only in the liver parenchyma had a clinical benefit from intensive chemotherapy with bevacizumab (disease control rate of 70%). Conclusion. This study confirmed a favourable safety profile and tolerability in terms of the incidence and severity of adverse and serious adverse events. High rates of resectability in both groups of patients, initially unresectable and potentially resectable, reflect the heterogeneity of criteria in decision making about liver resection and emphasize the need for establishing multisciplinary oncology teams and following the generally accepted criteria.