Treatment Of Bleeding Episodes Research Articles

Utilizing artificial intelligence for the detection of hemarthrosis in hemophilia using point-of-care ultrasonography

BackgroundRecurrent hemarthrosis and resultant hemophilic arthropathy are significant causes of morbidity in persons with hemophilia despite the marked evolution of hemophilia care. Prevention, timely diagnosis, and treatment of bleeding episodes are key. However, a physical examination or a patient’s assessment of musculoskeletal pain may not accurately identify a joint bleed. This difficulty is compounded as hemophilic arthropathy progresses. ObjectivesOur system aims to utilize artificial intelligence and ultrasonography (US; point-of-care and handheld) to enable providers, and ultimately patients, to detect joint bleeds at the bedside and at home. We aimed to develop and assess the reliability of artificial intelligence algorithms in detecting and segmenting synovial recess distension (SRD; an indicator of disease activity) on US images of adult and pediatric knee, elbow, and ankle joints. MethodsA total of 12,145 joint exams, comprising 61,501 US images from 7 international healthcare centers, were collected. The dataset included healthy participants and adult and pediatric persons with hemophilia, with and without SRD. Images were manually labeled by 2 experts and used to train binary convolutional neural network classifiers and segmentation models. Metrics to evaluate performance included accuracy, sensitivity, specificity, and area under the curve. ResultsThe algorithms exhibited high performance across all joints and all cohorts. Specifically, the knee model showed an accuracy of 97%, sensitivity of 96%, specificity of 97%, and an area under the curve of 0.97 in SRD. High Dice coefficients (80%-85%) were achieved in segmentation tasks across all joints. ConclusionThis technology could assist with the early detection and management of hemarthrosis in hemophilia.

Efficacy and safety of recombinant porcine factor VIII in Japanese patients with acquired hemophilia A

Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies inhibiting human factor VIII (hFVIII). This phase II/III open-label study evaluated the safety and efficacy of recombinant porcine factor VIII (rpFVIII, susoctocog alfa) in adults with AHA and severe bleeding episodes in Japan (NCT04580407). The initial rpFVIII dose was 200 U/kg, with subsequent doses based on clinical measures including plasma FVIII activity. The primary efficacy endpoint was the proportion of severe bleeding episodes with a positive response to rpFVIII therapy 24 h after treatment initiation. Five patients were eligible for, and completed, rpFVIII treatment (age group: 60s–80s; median hFVIII inhibitor: 52 BU/mL; porcine FVIII [pFVIII] inhibitor: 3/5 patients). The median (range) total dose/patient was 548.4 (198–1803) U/kg with a median 3.0 infusions/patient. All patients responded positively to rpFVIII therapy at 24 h regardless of baseline pFVIII inhibitor status. rpFVIII treatment was well tolerated with no adverse events of special interest such as thromboembolic events or de novo pFVIII inhibitors. This study supports the use of rpFVIII as a novel therapy in the clinical management of patients with AHA in Japan. rpFVIII was approved for treating bleeding episodes in adults with AHA in Japan in 2024.

Efanesoctocog Alfa Prophylaxis for Children with Severe Hemophilia A

BackgroundOnce-weekly efanesoctocog alfa provides high sustained factor VIII activity with superior bleeding prevention as compared with prestudy factor VIII prophylaxis in previously treated patients 12 years of age or older with severe hemophilia A. Data on outcomes of efanesoctocog alfa treatment in children younger than 12 years of age with severe hemophilia A are limited.MethodsWe conducted a phase 3, open-label study involving previously treated patients younger than 12 years of age with severe hemophilia A. Patients received prophylaxis with once-weekly efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. The primary end point was the occurrence of factor VIII inhibitors (neutralizing antibodies against factor VIII). Secondary end points included annualized rates of treated bleeding episodes, bleeding treatment, safety, and pharmacokinetics.ResultsA total of 74 male patients were enrolled (38 with an age of <6 years and 36 with an age of 6 to <12 years). No factor VIII inhibitors developed. Most adverse events were nonserious. No serious adverse events that were assessed by the investigator as being related to efanesoctocog alfa were reported. In the 73 patients treated according to the protocol, the median and model-based mean annualized bleeding rates were 0.00 (interquartile range, 0.00 to 1.02) and 0.61 (95% confidence interval, 0.42 to 0.90), respectively. A total of 47 patients (64%) had no treated bleeding episodes, 65 (88%) had no spontaneous bleeding episodes, and 61 (82%) had no episodes of bleeding into joints. A total of 41 of 43 bleeding episodes (95%) resolved with one injection of efanesoctocog alfa. Mean factor VIII activity at steady state was more than 40 IU per deciliter for 3 days and more than 10 IU per deciliter for almost 7 days after dose administration. The geometric mean terminal half-life was 40.0 hours.ConclusionsIn children with severe hemophilia A, once-weekly prophylaxis with efanesoctocog alfa provided high sustained factor VIII activity in the normal to near-normal range (>40 IU per deciliter) for 3 days and more than 10 IU per deciliter for almost 7 days after administration, leading to effective bleeding prevention. Efanesoctocog alfa was associated with mainly nonserious adverse events. (Funded by Sanofi and Sobi; XTEND-Kids ClinicalTrials.gov number, NCT04759131.)

Plain language summary of efanesoctocog alfa for patients with severe hemophilia A

What is this summary about? This is a plain language summary of a clinical research study called XTEND-1. The study looked into how safe and effective a medicine called efanesoctocog alfa is for people with severe hemophilia A. Hemophilia A is a genetic condition in which the body does not produce enough or makes dysfunctional clotting factor VIII (eight) – a protein that is essential for blood clotting. People with hemophilia A are prone to dangerous bleeding, particularly internally and into their joints and muscles. How was the research done? The XTEND-1 study compared two ways of using the medication to treat bleeding episodes: (1) injecting it once a week for 12 months as a prophylaxis (regular preventative) treatment, or (2) injecting it as needed for 6 months, followed by weekly prophylaxis treatment for a further 6 months. What did the research find out? People who had prophylaxis treatment with efanesoctocog alfa injections for one year saw a significant reduction in the amount of bleeding they experienced compared to their pre-study prophylaxis treatment. The effects of the treatment also lasted longer, with higher factor VIII levels for longer, than previous prophylaxis treatment and less frequent injections were needed. There was a significant reduction in the amount of bleeding in people taking once-weekly prophylaxis treatment compared to ‘as needed’ treatment.

Treatment of Bleeding Episodes with Efanesoctocog Alfa in Children with Severe Hemophilia A in the XTEND-Kids Phase 3 Study

Introduction Efanesoctocog alfa (formerly BIVV001) is a new class of high sustained factor VIII (FVIII) replacement therapy, composed of a single recombinant FVIII protein fused to dimeric Fc protein, 2 XTEN polypeptides, and the D'D3 domain of von Willebrand factor (VWF), designed to overcome the endogenous VWF-imposed half-life ceiling. The XTEND-Kids (NCT04759131) study demonstrated once-weekly efanesoctocog alfa was well tolerated and provided effective treatment of and protection from bleeds in previously treated patients &amp;lt;12 years old with severe hemophilia A. Here, we provide a detailed report on efanesoctocog alfa as a treatment for bleeds during XTEND-Kids. Methods Previously treated patients &amp;lt;12 years old (≥150 exposure days [EDs] for patients 6 to &amp;lt;12 years of age and ≥50 EDs for patients &amp;lt;6 years old) with severe hemophilia A (&amp;lt;1 IU/dL [&amp;lt;1%] endogenous FVIII activity or a documented genotype associated with severe hemophilia) received efanesoctocog alfa 50 IU/kg once weekly for 52 weeks. In line with the study protocol, bleeds were treated with a single dose of efanesoctocog alfa (50 IU/kg). Additional doses (30 or 50 IU/kg, every 2-3 days) could be considered if needed. For minor/moderate bleeds occurring within 2-3 days of a recent prophylactic dose, a 30 IU/kg dose could also be used. The number and location of bleeds, as well as dose and number of efanesoctocog alfa injections required to resolve them were recorded. Patient assessment of the response to the first injection for treating a bleed was evaluated using the 4-point International Society on Thrombosis and Haemostasis (ISTH) scale (excellent, good, moderate, and none). Results Of 74 patients in XTEND-Kids, 73 were included in these post hoc analyses, including 38 subjects &amp;lt;6 years of age. One subject in the 6 to &amp;lt;12 group was excluded from these analyses as he did not receive weekly prophylaxis treatment as specified in the protocol, instead receiving intense consolidation treatment (2-3 injections per week for ~4 months) following 2 traumatic self-reported hip bleeds (however, no signs of bleeding or joint damage were observed by magnetic resonance imaging during the consolidation treatment period). The mean (SD) total number of EDs was 52.3 (6.83) for the overall population. The mean (95% confidence interval [CI]) estimated annualized bleed rate (ABR) was 0.61 (0.42-0.90). The mean (95% CI) annualized spontaneous, traumatic, and joint bleed rates were 0.16 (0.08-0.31), 0.40 (0.24-0.65), and 0.30 (0.16-0.57), respectively. Eighty-six percent of participants (n=63) had ≤1 bleed, including 64% (n=47) with no overall bleeds; 88% (n=64) had no spontaneous bleeds and 84% (n=61) had no joint bleeds. There were 43 bleeds treated with efanesoctocog alfa, of which 11 were reported as spontaneous (26%), 28 as traumatic (65%), and 4 (9%) were of unknown etiology (Table). The most common locations for bleeds were the joints (n=21, 49%) and skin/mucosa (n=15, 35%). The rate of bleeding events per week throughout the study remained consistently low (Figure). The mean (SD) duration between a treated bleed and nearest injection taken prior to that bleed was 4.7 (1.95) days, with a mean of 4.5 (1.56) days for a spontaneous bleed and 4.8 (2.12) for traumatic bleeds. A single injection was sufficient to resolve 95% of bleeds, and no bleed required more than 2 injections for resolution. The median (interquartile range) total dose required to resolve a bleed was 52.6 (50.0-55.8) IU/kg. Among first injections for bleeding episodes with an evaluation of response by participants (n=37), the vast majority (n=36, 97%) were rated as excellent or good. Conclusions A single dose of efanesoctocog alfa 50 IU/kg resolved 95% of bleeds in children &amp;lt;12 years of age, regardless of type or location. The hemostatic efficacy of efanesoctocog alfa was rated as excellent or good for nearly all evaluated first injections (97%). Once-weekly efanesoctocog alfa provided efficient prophylaxis with no bleeds in 64% of participants, and consistently low ABRs among all types and locations of bleeds. Efanesoctocog alfa provided effective treatment and prevention of bleeds in previously treated children &amp;lt;12 years of age with severe hemophilia A.

Plain language summary of the GENEr8-1 clinical trial of valoctocogene roxaparvovec gene therapy for hemophilia A

What is this summary about? In healthy people, a protein called factor VIII (FVIII) helps blood to clot and prevents excessive bleeding. People with hemophilia A lack FVIII because a faulty F8 gene is giving the wrong instructions to the liver cells that make it. Valoctocogene roxaparvovec (ROCTAVIAN™) is a gene therapy designed to transfer working copies of the F8 gene into liver cells. This summary describes the GENEr8-1 study, which looked at how well valoctocogene roxaparvovec works for treating people with severe hemophilia A compared with their usual FVIII replacement therapy, and its safety. 134 men received valoctocogene roxaparvovec; results from the first 2 years are reported. What were the results? Valoctocogene roxaparvovec significantly improved bleed control in men with severe hemophilia A. A single infusion reduced average treated bleeding episodes per year from almost 5 while on FVIII prophylaxis to less than one after gene therapy. Eight out of every 10 participants had no bleeds needing treatment and 9 out of every 10 had no joint bleeds needing treatment; FVIII levels improved to normal or mild hemophilia ranges. All except 6 participants remained off regular FVIII prophylaxis for at least 2 years. All participants had at least one side effect and 22 (16%) reported serious adverse events. Nine out of every 10 participants (89%) showed increased blood levels of liver enzymes, indicating an expected immune response to the product's viral shell; this was manageable with steroids. Other common side effects included headache (41%), joint pain (40%), feeling sick (38%), and side effects to steroids (60%). What do the results mean? After a one-time dose of valoctocogene roxaparvovec, people with severe hemophilia A start producing their own FVIII and require fewer or no FVIII injections to protect them from bleeds. Results showing bleed control for at least 2 years have led to approvals of valoctocogene roxaparvovec in Europe and the USA for use in adults with severe hemophilia A who do not have antibodies against FVIII or AAV type 5. How well valoctocogene roxaparvovec works and the side effects over a longer period are still being studied.

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.

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Recombinant von Willebrand factor (rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA) and several plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrates are available for treating bleeding episodes in patients with von Willebrand disease (VWD). To develop population pharmacokinetic (PK)/pharmacodynamic (PD) models that describe VWF:ristocetin cofactor (VWF:RCo) activity and its relationship with FVIII activity (FVIII:C) over time following intravenous administration of either rVWF or a pdVWF/FVIII concentrate (VWF:RCo/FVIII:C 2.4:1) in patients with VWD; to use the final PK/PD models for an in silico comparison of rVWF and pdVWF/FVIII. The population PK model for rVWF was based on data from four clinical studies in which rVWF was administered to adult patients with VWD type 1, 2 or 3 (phase 1: NCT00816660; phase 3: NCT01410227 and NCT02283268) or severe hemophilia A (phase 1: EudraCT 2011-004314-42). The PK and PK/PD models for pdVWF/FVIII were based on data from the phase 1 study (NCT00816660) in patients with type 3 VWD who received either rVWF plus recombinant FVIII (rFVIII, octocog alfa, ADVATE®, Takeda Pharmaceuticals USA, Lexington, MA, USA) or pdVWF/FVIII. There was a marked difference in clearance following rVWF administration compared with pdVWF/FVIII in type 3 VWD, leading to a ~1.75 longer mean residence time (ie, persistence of VWF:RCo activity in the body) and half-life for rVWF versus pdVWF/FVIII. Simulations showed that following repeated administration of rVWF (50 IU/kg), a FVIII:C activity of >40 IU/dL can be maintained for the full 72 h dosing interval. The slower elimination of VWF:RCo following rVWF administration results in a prolonged effect on FVIII turnover compared with pdVWF/FVIII administration.

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.

Economic Evaluation of Immune Tolerance Induction in Children With Severe Hemophilia A and High-Responding Inhibitors: A Cost-Effectiveness Analysis of Prophylaxis With Emicizumab

ObjectiveThis study aimed to measure the cost-effectiveness of prophylaxis with emicizumab in PsHAhri on ITI in Brazil. MethodsA cost-effectiveness modeling analysis was used to estimate the costs per PsHAhri on ITI and the number of prevented bleedings from undertaking one intervention (prophylaxis with BpA) over another (prophylaxis with emicizumab), based on the Brazilian Ministry of Health perspective. Costs of ITI with recombinant FVIII, prophylaxis with BpA or emicizumab, and treated bleeding episodes with BpA costs were evaluated for PsHAhri who had ITI success or failure. This study was conducted with the perspective of the Brazilian Ministry of Health (payer). ResultsDuring ITI, prophylaxis with BpA cost US $924 666/PsHAhri/ITI, whereas prophylaxis with emicizumab cost US $488 785/PsHAhri/ITI. During ITI, there was an average of 9.32 bleeding episodes/PsHAhri/ITI when BpA were used as prophylaxis and 0.67 bleeding/PsHAhri/ITI when emicizumab was used. By univariate deterministic sensitivity analysis, emicizumab remained dominant whichever variable was modified. ConclusionIn this study, prophylaxis with emicizumab during ITI is a dominant option compared with prophylaxis with BpA during ITI.

Nonacog Alfa for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Patients with Moderately Severe or Severe Hemophilia B in India

PurposeHemophilia B is an X-linked congenital bleeding disorder caused by a deficiency of coagulation factor IX (FIX) clotting activity. This study evaluated safety and efficacy of nonacog alfa, a recombinant human blood coagulation FIX replacement product, in males aged 12–65 years with hemophilia B (FIX activity ≤ 2%) with or without inhibitors in India.MethodsIn this multicenter, open-label, post-approval phase 4 study, participants were treated for up to 8 weeks, with up to a 4-week screening period and a subsequent post-treatment 28-day safety observation period. Intravenous nonacog alfa 40 IU/kg (range 13–78 IU/kg) was administered at intervals of 3–4 days, in accordance with the approved local product document.ResultsA total of 25 participants were enrolled and completed the study. No participants developed FIX inhibitors during the study, experienced treatment-related adverse events (AEs) or serious AEs, or developed a thrombotic event and/or hypersensitivity reaction. No participants experienced bleeding events requiring on-demand treatment with nonacog alfa. Seventeen bleeding episodes (16 spontaneous and 1 traumatic) were reported in 10 participants; all occurred post treatment, with the exception of a minor gum-bleeding event, and were managed without treatment. The mean (SD) annualized total factor consumption (TFC) per patient was 224,582 (75,527) IU; the mean (SD) annualized TFC by weight per patient was 3639 (573) IU/kg.ConclusionNonacog alfa was safe and effective for the prevention of hemorrhagic episodes in Indian males with congenital, severe hemophilia B. No participants developed FIX inhibitors, and no new safety signals were reported.

Moroctocog Alfa (AF-CC) for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Patients with Hemophilia A in India.

Hemophilia A is an X-linked congenital disorder, characterized by factor VIII (FVIII) deficiency. Globally, India has the highest population of patients with hemophilia, and there is a clear unmet need for appropriate and effective treatment for this patient population. This multicenter, open-label, post-approval study evaluated the safety and efficacy of moroctocog alfa in patients with moderate or severe congenital hemophilia A in India. Intravenous moroctocog alfa was administered 30 ± 5 IU/kg 3 times weekly for bleeding prophylaxis, according to the local product document. Participants were treated for up to 8 weeks, with an up to 4-week screening period and a subsequent post-treatment, 28-day safety observation period. Patients continued in the study until at least 24 exposure days or a period of up to 8 weeks on moroctocog alfa. A total of 50 participants were enrolled, and 48 (85.7%) completed the study. No participants developed FVIII inhibitors during the study. The mean (SD) annualized bleeding rate during moroctocog alfa prophylaxis was 0.79 (2.0) with a median (range) of 0.00 (0.0, 6.8). The mean (SD) annualized total factor consumption (TFC) per participant was 287,432 (93,866) IU; the mean (SD) annualized TFC by weight per participant was 4176 (858) IU/kg. Moroctocog alfa was well tolerated with no reported treatment-emergent adverse event-related dose reductions, discontinuations, or serious adverse events. Moroctocog alfa was safe, effective, and well tolerated in Indian participants with congenital moderate to severe hemophilia A. No participant developed FVIII inhibitors during the study.

Pharmacokinetics, Efficacy and Safety Evaluation of FRSW107 in Previously Treated Hemophilia a Patients: A Multicentre, Open-Label, Non-Randomized Phase III Study

Background: FRSW 107, a novel homodimer recombinant factor VIII (rFVIII) Fc fusion protein, is the first domestic extended half-life (EHL) rFVIII under development in China，and is currently at stage of Biologics License Application (BLA) in NMPA for the prophylaxis and treatment of bleeding episodes in adolescent and adult (≥12 yr) with hemophilia A (HA). Aims: This phase III (NCT04456387, CTR20201212), open-label, non-randomized, multicenter trial aimed to evaluate the pharmacokinetics (PK), safety, and clinical efficacy of FRSW 107 for prophylaxis and treatment of bleeding in previously treated HA patients ≥12 yr. Methods: Eligible patients included male severe HA (FVIII:C< 1%) ≥12 yr, previous treatment with FVIII concentrates for ≥150 exposure days (EDs), and absence of FVIII inhibitors (＜0.6 Bethesda Units/mL). A total of 119 patients received FRSW 107 for prophylaxis treatment (n=83) or on-demand treatment (n=36). The patients in the prophylaxis group were administered one dose of 50 IU/kg of FRSW 107 every three days for at least 50 EDs for a minimum period of 6 months, and the primary efficacy endpoint was annualized bleeding rate (ABR). The patients in the on-demand treatment group received 30 to 50 IU/kg of FRSW 107 over 6 months, according to the severity and location of the bleeding, and the primary efficacy endpoint was hemostatic effect (excellent, good). The single-dose and repeat dose PK parameters of 15 patients in the prophylaxis group were analyzed at ED1 and ED35, respectively. Results: In the prophylaxis group, the mean and median annualized bleeding rate (ABR) were 1.61±3.74 and 0.00 (IQR, 0.00-2.02), decreased by 95.01% versus the baseline 32.24±23.98 and 26.00 (IQR, 16.00-46.00), and 56 (67.5%) patients had no bleeds during the trial. Detailed ABR data for prophylaxis group was included in the table below. In the on-demand treatment group, hemostatic efficacy was rated as "excellent” or "good” for 98.9% of bleeds. 97.9% of 721 reported bleeds were treated with ≤2 injections. No FVIII inhibitors have been reported in this study. Drug-related adverse events (AEs) occurred in 10.1% of the patients. No SAE was judged to be related to FRSW107 treatment. No thromboembolic events were reported, and there are no unexpected safety concerns. The terminal half-life of FRSW 107 ranged between 20 to 22 hours. The incremental recovery (IR) was approximately 2.14 (IU/dL)/(IU/kg). The PK parameters and profiles remained consistent between ED1 and the repeated dosing at ED35. Conclusions: The data indicate that FRSW 107 was safe and effective for prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult HA patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Multiple Ascending Dose Study of Mim8 in Patients with Severe Hemophilia a with or without Factor VIII Inhibitors

Introduction: Mim8 is a subcutaneously administered, activated factor VIII (FVIIIa) mimetic bispecific antibody that bridges factors IXa and X, and is currently in clinical development for patients with hemophilia A with or without inhibitors. Mim8 has demonstrated hemostatic efficacy in animal bleeding models, with preclinical data suggesting a higher potency than a sequence-identical analog of emicizumab. FRONTIER 1 (EudraCT:2019-000465-20; NCT04204408) is a 2-part phase 1/2 study of Mim8, consisting of single ascending dose and multiple ascending dose (MAD) parts in healthy participants and patients with hemophilia A, respectively. Here, we report results from all 5 cohorts of the MAD part of the study, which investigates the safety and tolerability, as well as the pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous Mim8 in patients with severe hemophilia A, with or without FVIII inhibitors. Methods: Patients with hemophilia A were administered multiple ascending doses of Mim8 for 12 weeks, targeting average plasma concentrations of 1 µg/mL (cohort 1, once weekly [QW] dosing), 3 µg/mL (cohort 2, QW dosing), 9 µg/mL (cohort 3, QW dosing; cohort 4, once every 4 weeks [Q4W] dosing), or 20 µg/mL (cohort 5, QW dosing). Patients in cohorts 3 and 4 were randomized 1:1 to either QW or Q4W dosing, respectively. Adverse events, serious adverse events, and adverse events of special interest were monitored, and the assessment of PK and PD at steady state was undertaken on days 57-64 (QW) or days 57-85 (Q4W). Preliminary efficacy was assessed as an exploratory endpoint as number of treated bleeding episodes over 12 weeks of treatment. Results: Forty-two patients in total were included in the 5 MAD cohorts (cohort 1, n=7; cohort 2, n=9; cohort 3, n=8; cohort 4, n=8; cohort 5, n=10). Four (9.5%) patients had FVIII inhibitors. All patients were males older than 12 years of age (mean [SD] age of 34 [13] years). Mim8 was well tolerated, with no evidence for dose impacting the rate, causality, type, or severity of adverse events (Table 1). Injection site reactions occurred in <1% of injections (4 mild injection site reactions in 4 [9.5%] patients) and no anti-Mim8 antibodies were observed. There was 1 serious adverse event (moderate noncardiac chest pain), deemed to be unrelated to Mim8. One patient was withdrawn from the study due to a hypersensitivity reaction, but there was no lack of treatment efficacy, and the symptoms resolved when treatment was discontinued. Steady-state median prothrombin fragment 1+2 levels increased in a dose-dependent manner (cohort 1, 93 pmol/L; cohort 2, 159 pmol/L; cohort 3, 372 pmol/L; cohort 4, 346 pmol/L; cohort 5, 460 pmol/L). Other coagulation parameters showed no dose-dependent changes from baseline to week 12. Steady-state Mim8 area under the curve and maximum concentration increased with dose, consistent with dose proportionality (Figure 1). PK profiles were similar between patients with and without inhibitors. Mean-concentrations at steady-state PK concentrations were comparable between QW (cohort 3) and Q4W (cohort 4) dosing, which targeted similar Mim8 plasma concentrations. PD was monitored at steady state using a thrombin generation assay, and peak thrombin increased with dose, with comparable peak thrombin heights between cohorts 3 and 4. Six out of 7 patients reported treated bleeds in cohort 1, while few patients had treated bleeds in the higher dose cohorts. All bleeds reported in cohorts 2-4 were traumatic non-joint bleeds Conclusion: Data from the MAD part of FRONTIER 1 showed proof of concept and demonstrated a good safety profile, thereby providing support for the continued clinical development of Mim8 for patients with hemophilia, with and without inhibitors. No thrombotic events and no antibody development were observed. PK and PD properties were consistent with dose proportionality, supporting both QW and Q4W dosing. Additionally, the study provided some encouraging data regarding the efficacy of Mim8, with few patients reporting bleeds beyond the lowest dose cohort. The study has continued into an extension phase. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Analytical Performance of Different Laboratory Methods for Measuring Susoctocog-Alfa.

Recombinant porcine factor VIII (rpFVIII) is indicated for treating bleeding episodes in acquired haemophilia A, but there are few data regarding laboratory methods to adequately monitor treatment. This study involving three Italian laboratories aimed to evaluate the analytical performance of different assays for measuring rpFVIII. Five spiked rpFVIII samples (0.5–1.5 IU/mL) were analysed on three days, in triplicate, with eleven combinations of reagents (Werfen, Boston, MA, USA: SynthasIL and SynthaFax for one-stage assay, Chromogenix Coamatic FVIII for chromogenic assay), FVIII depleted plasmas (with or without von Willebrand factor—VWF) and calibrators (HemosIL human calibrator plasma, porcine calibrator diluted in FVIII deficient plasma with or without VWF). The assays were performed on ACL TOP analysers (Werfen, Boston, MA, USA). Intra- and inter-assay and inter-laboratory Coefficient of Variation (CV%) were calculated together with percentage of recovery (% recovery) on the expected value. The results showed that the reagent combinations reaching satisfactory analytical performance are: SynthasIL/human calibrator/deficient plasma+VWF (total recovery 99.4%, inter-laboratory CV 4.04%), SynthasIL/porcine calibrator/deficient plasma+VWF (total recovery 111%, inter-laboratory CV 2.75%) and Chromogenic/ porcine calibrator/deficient plasma+VWF (total recovery 96.6%, inter-laboratory CV 8.32%). This study highlights that the use of porcine standard (when available) and FVIII deficient plasma with VWF should be recommended.

Desmopressin for bleeding in non‐severe hemophilia A: Suboptimal use in a real‐world setting

BackgroundDesmopressin is an important treatment option in nonsevere hemophilia A because it has several benefits compared with factor (F) concentrates, including no inhibitor risk and much lower costs. Despite these advantages, data are limited on the real‐world use of desmopressin in the treatment of bleeds. ObjectiveTo describe the clinical use of desmopressin in relation to other therapeutic modalities in the treatment of bleeding episodes in patients with nonsevere hemophilia A. MethodsPatients with nonsevere hemophilia A aged 12–55 years were included from the DYNAMO cohort study. Data on the desmopressin test response and treated bleeding events in the period January 2009 to July 2020 were retrospectively collected from medical files. An adequate desmopressin test response was defined based on a peak FVIII level of ≥30 IU/dl. ResultsA total of 248 patients with a median age of 38 years (interquartile range 25–49) were included. An adequate desmopressin test response was documented in 25% and 73% of patients with moderate and mild hemophilia, respectively. In adequate responders, 51% of bleeds were exclusively treated with FVIII concentrates, 24% exclusively with desmopressin, 21% with a combination of both and 4% with other treatments. In 54% of bleeds treated with a single dose of factor concentrates, the expected FVIII level after desmopressin exceeded the level targeted. ConclusionMost bleeds in patients with an adequate response to desmopressin are treated with factor concentrates. These findings may indicate a suboptimal use of desmopressin and that barriers to the use of desmopressin should be explored.

Non-factor therapies for bleeding disorders: A primer for the general haematologist.

Management of patients with severe bleeding disorders, particularly haemophilia A and B, and to a lesser extent, von Willebrand disease, has come on leaps and bounds over the past decade. Until recently, patients relied upon the administration of factor concentrates to prevent or treat bleeding episodes. Factor administration requires intravenous access and, in up to one‐third of patients, leads to the development of neutralising antibodies, or inhibitors, which are associated with more frequent bleeding episodes and higher morbidity. Novel non‐factor therapies may offer a solution to these unmet needs. In this review, we discuss the factor mimetics, particularly emicizumab, and the rebalancing agents, which inhibit antithrombin, tissue factor pathway inhibitor and activated protein C, and novel treatments to enhance von Willebrand factor levels. We review the available trial data, unanswered questions and challenges associated with these new treatment modalities. Finally, we provide practical management algorithms to aid the general haematologist when faced with a patient receiving emicizumab who requires surgery or may develop bleeding.

Efficacy and safety of von Willebrand factor concentrate almost devoid of factor VIII (Wilfactin®) in paediatric patients under 6 years of age with severe von Willebrand disease.

Plasma-derived von Willebrand factor (VWF) (Wilfactin®, LFB, France) was developed for prophylaxis and treatment of haemorrhages in both adults and adolescents with von Willebrand disease (VWD). Replacement therapy in paediatric patients is a key element of the clinical trial programme. Patients aged <6 years with severe VWD were enrolled in a multinational, open-label study to evaluate the in vivo recovery for Wilfactin®, and its efficacy in preventing and treating bleeding episodes and during surgery. Overall haemostatic efficacy based on a 4-point scale was assessed by investigators. The treatment period ≥18 months investigated the long-term safety. Nine patients, including 7 with type 3 VWD were exposed to treatment with Wilfactin® for up to 4.2 years. Recovery of VWF in 7 patients (n=5 type 3, n=1 type 2, n=1 type 1) was 1.8±0.4 IU/dL per IU/kg. Of the 62 bleeds, 89% were controlled with one (73%) or two (16%) infusions of Wilfactin®. The median dose per infusion was 54 IU/kg. A factor VIII dose was co-administered in 1.6% of bleeds. "Excellent"/"Good" haemostatic efficacy was achieved in 90.3% of episodes. Six patients underwent 11 minor surgical interventions. Treatment duration was 1 day (range: 1-6 days) with a dose administered 30-60 minutes before procedure of 56 IU/kg (range: 41-106 IU/kg). Haemostasis was rated as "Excellent" in all surgeries. During 4-year prophylactic treatment in one patient, breakthrough bleeds were reported in 2.2% of infusions. No VWF inhibitors, thromboembolic events or allergic/anaphylactic-type reactions were observed following a total exposure of 770 days. The results show that Wilfactin® provides a safe and effective treatment in patients <6 years of age with severe VWD.

Hemophilia: The Past, the Present, and the Future.

Hemophilia: The Past, the Present, and the Future.