-
1.
Subcutaneous marzeptacog alfa (activated) for on-demand treatment of bleeding events in subjects with haemophilia A or B with inhibitors
Faraj, A., Nyberg, J., Blouse, G. E., Knudsen, T., Simonsson, U. S. H.
Clinical pharmacology and therapeutics. 2024
Abstract
Marzeptacog alfa (MarzAA) is under development for subcutaneous treatment of episodic bleeds in hemophilia A/B patients and was studied in a Phase 3 trial evaluating MarzAA compared to standard-of-care (SoC) for on-demand use. The work presented here aimed to evaluate MarzAA and SoC treatment of bleeding events on a standardized 4-point efficacy scale (poor, fair, good and excellent). Two continuous-time Markov modeling approaches were explored; a four-state model analyzing all four categories of bleeding improvement and a two-state model analyzing a binarized outcome (treatment failure [poor/fair], and treatment success [good/excellent]). Different covariates impacting improvement of bleeding episodes as well as a putative relationship between MarzAA exposure and improvement of bleeding episodes were evaluated. In the final four-state model, higher baseline diastolic blood pressure and higher age (>33 years of age) were found to negatively and positively impact improvement of bleeding condition, respectively. Bleeding events occurring in knees and ankles were found to improve faster than bleeding events at other locations. The covariate effects had most impact on early treatment success (=<3 hours) whereas at later timepoints (>12 hours), treatment success was similar for all patients indicating that these covariates might be clinically relevant for early treatment response. A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (p< 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route.
-
2.
BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial
Ljung, R., Chan, A. K. C., Glosli, H., Afonja, O., Becker, B., Tseneklidou-Stoeter, D., Mancuso, M. E., Saulyte-Trakymiene, S., Kenet, G.
Thrombosis and Haemostasis. 2023;123(1):27-39
Abstract
INTRODUCTION BAY 81-8973, a full-length recombinant factor VIII for hemophilia A treatment, has been extensively evaluated in previously treated patients in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials. AIM: To assess BAY 81-8973 efficacy and safety when used for bleed prophylaxis and treatment in previously untreated/minimally treated patients (PUPs/MTPs). METHODS In this phase III, multicenter, open-label, uncontrolled study, PUPs/MTPs (<6 years old) with severe hemophilia A received BAY 81-8973 (15-50 IU/kg) at least once weekly as prophylaxis. Primary efficacy endpoint was the annualized bleeding rate (ABR) within 48 hours after prophylaxis infusion. Adverse events and immunogenicity were assessed. Patients who developed inhibitors were offered immune tolerance induction (ITI) treatment in an optional extension phase. RESULTS Fifty-two patients were enrolled, with 43 patients (mean age: 13.6 months) treated. Median (interquartile range) ABR for all bleeds within 48 hours of prophylaxis infusion was 0.0 (0.0-1.8) among patients without inhibitors (n = 20) and 0.0 (0.0-2.2) among all patients. As expected, inhibitors were the most frequent treatment-related adverse event (high titer: 17 [39.5%] patients; low titer: 6 [13.9%] patients). Six of 12 patients who underwent ITI treatment in the extension phase (high titer [n = 5], low titer [n = 1]) achieved a negative inhibitor titer. CONCLUSION BAY 81-8973 was effective for bleed prevention and treatment in PUPs/MTPs. The observed inhibitor rate was strongly influenced by a cluster of inhibitor cases, and consequently, slightly higher than in other PUP/MTP studies. Overall, the BAY 81-8973 benefit-risk profile remains unchanged and supported by ongoing safety surveillance. Immune tolerance can be achieved with BAY 81-8973.
-
3.
Real-world evidence on efmoroctocog alfa in patients with haemophilia A: A systematic literature review of treatment experience in Europe
Blatný J, Nielsen EM, Reitzel SB, McMillan AC, Danø A, Bystrická L, Kragh N, Klamroth R
Haemophilia : the official journal of the World Federation of Hemophilia. 2023
Abstract
INTRODUCTION The real-world effectiveness of the efmoroctocog alfa (recombinant FVIII Fc fusion protein, a rFVIIIFc) has been investigated in numerous studies, however, currently, there exists no comprehensive collection of the existing real-world evidence (RWE) on the performance of prophylactic use of rFVIIIFc. AIM: The aims of this systematic literature study were to identify, review, evaluate and collate the RWE of prophylactic rFVIIIFc for patients with haemophilia A reported in Europe. METHODS We searched Medline and Embase from 2014 to February 2022 to identify publications reporting the effectiveness of rFVIIIFc in patients with haemophilia A. The outcomes of interest were annualised bleeding rates (ABR, AjBR, AsBR), injection frequency, factor consumption, adherence, development of inhibitors and quality-of-life measures. RESULTS 46 eligible publications (eight full-text articles) were included. rFVIIIFc showed a low ABR in patients with haemophilia A. Studies assessing treatment switching from a standard half-life (SHL) treatment to rFVIIIFc found that the ABR and consumption were reduced in most patients. Studies assessing rFVIIIFc effectiveness reported a median ABR between 0.0 and 2.0 with median injections per week ranging between 1.8 and 2.4 and median doses between 60 and 105 IU/kg/week. Of the studies assessing inhibitor development, only one study reported an incidence of a low titre inhibitor, and no patients developed clinically significant inhibitors. CONCLUSION rFVIIIFc prophylaxis treatment results in a low ABR across studies in patients with haemophilia A in a European real-world setting, which correlates with findings from clinical trials assessing the efficacy of rFVIIIFc in patients with haemophilia A.
-
4.
Determinants of successful immune tolerance induction in hemophilia A: systematic review and meta-analysis
Oomen I, Camelo RM, Rezende SM, Voorberg J, Mancuso ME, Oldenburg J, Carcao M, Matino D, Lillicrap D, Fischer K, et al
Research and practice in thrombosis and haemostasis. 2023;7(1):100020
Abstract
BACKGROUND Immune tolerance induction (ITI) aims to eradicate anti-factor VIII (FVIII) antibodies (inhibitors) in persons with hemophilia A. However, this burdensome treatment fails in 10% to 40%. To estimate the chance of ITI success in clinical decision making, it is important to identify the predictors of ITI success. OBJECTIVES We performed a systematic review and meta-analysis to summarize the current evidence on determinants of ITI outcome in persons with hemophilia A. METHODS A literature search was conducted to identify randomized controlled trials, cohort, or case-control studies reporting on the predictors for ITI outcome in persons with hemophilia A. The main outcome was ITI success. Methodological quality was assessed using an adapted Joanna Briggs Institute checklist, rating as high if ≥11 of 13 criteria were met. Pooled odds ratios (ORs) for ITI success were calculated for each determinant. ITI success was defined as negative inhibitor titer (<0.6 BU/mL), FVIII recovery ≥66% of expected, and FVIII half-life ≥6 hours in 16 (59.3%) studies. RESULTS We included 27 studies, involving 1,734 participants. Methodological quality of 6 (22.2%) studies (418 participants) was rated as high. Twenty different determinants were assessed. Historical peak titer ≤100 BU/mL (compared with >100 BU/mL, OR, 1.7; 95% CI, 1.4-2.1), pre-ITI titer ≤10 BU/mL (compared with >10 BU/mL, OR, 1.8; 95% CI, 1.4-2.3), and peak titer during ITI ≤100 BU/mL (compared with >100 BU/mL, OR, 2.7; 95% CI, 1.9-3.8) were associated with a higher chance of ITI success. CONCLUSION Our results suggest that determinants related to the inhibitor titer are associated with ITI success.
-
5.
Efanesoctocog Alfa Prophylaxis for Patients with Severe Hemophilia A
von Drygalski, A., Chowdary, P., Kulkarni, R., Susen, S., Konkle, B. A., Oldenburg, J., Matino, D., Klamroth, R., Weyand, A. C., Jimenez-Yuste, V., et al
The New England Journal of Medicine. 2023;388(4):310-318
Abstract
BACKGROUND Efanesoctocog alfa provides high sustained factor VIII activity by overcoming the von Willebrand factor-imposed half-life ceiling. The efficacy, safety, and pharmacokinetics of efanesoctocog alfa for prophylaxis and treatment of bleeding episodes in previously treated patients with severe hemophilia A are unclear. METHODS We conducted a phase 3 study involving patients 12 years of age or older with severe hemophilia A. In group A, patients received once-weekly prophylaxis with efanesoctocog alfa (50 IU per kilogram of body weight) for 52 weeks. In group B, patients received on-demand treatment with efanesoctocog alfa for 26 weeks, followed by once-weekly prophylaxis with efanesoctocog alfa for 26 weeks. The primary end point was the mean annualized bleeding rate in group A; the key secondary end point was an intrapatient comparison of the annualized bleeding rate during prophylaxis in group A with the rate during prestudy factor VIII prophylaxis. Additional end points included treatment of bleeding episodes, safety, pharmacokinetics, and changes in physical health, pain, and joint health. RESULTS In group A (133 patients), the median annualized bleeding rate was 0 (interquartile range, 0 to 1.04), and the estimated mean annualized bleeding rate was 0.71 (95% confidence interval [CI], 0.52 to 0.97). The mean annualized bleeding rate decreased from 2.96 (95% CI, 2.00 to 4.37) to 0.69 (95% CI, 0.43 to 1.11), a finding that showed superiority over prestudy factor VIII prophylaxis (P<0.001). A total of 26 patients were enrolled in group B. In the overall population, nearly all bleeding episodes (97%) resolved with one injection of efanesoctocog alfa. Weekly prophylaxis with efanesoctocog alfa provided mean factor VIII activity of more than 40 IU per deciliter for the majority of the week and of 15 IU per deciliter at day 7. Prophylaxis with efanesoctocog alfa for 52 weeks (group A) improved physical health (P<0.001), pain intensity (P = 0.03), and joint health (P = 0.01). In the overall study population, efanesoctocog alfa had an acceptable side-effect profile, and the development of inhibitors to factor VIII was not detected. CONCLUSIONS In patients with severe hemophilia A, once-weekly efanesoctocog alfa provided superior bleeding prevention to prestudy prophylaxis, normal to near-normal factor VIII activity, and improvements in physical health, pain, and joint health. (Funded by Sanofi and Sobi; XTEND-1 ClinicalTrials.gov number, NCT04161495.).
-
6.
The Impact of Recombinant Versus Plasma-Derived Factor VIII Concentrates on Inhibitor Development in Previously Untreated Patients With Hemophilia A: A 2021 Update of a Systematic Review and Meta-Analysis
Kohar K, Prayogo SA, Wiyono L
Cureus. 2022;14(6):e26015
-
-
-
Free full text
-
Editor's Choice
Abstract
Hemophilia A, the most common hereditary disorder, is caused by clotting factor deficiency. Challenges encountered in the current treatment of hemophilia A [factor VIII (FVIII) replacement therapy] due to inhibitor development have caused ineffective treatment as well as morbidity and mortality among patients. However, there are no studies comparing the two types of FVIII treatments in terms of inhibitor development rate. Therefore, we conducted this systematic review to devise a better treatment option with a lower risk of inhibitor development. The systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and by searching several databases. Data extraction on study characteristics and outcomes was conducted. Reviewers also conducted a risk of bias assessment on all studies. All eligible studies for quantitative analysis were then processed using RevMan 5.4.1 and the data was extrapolated into cumulative outcomes and expressed in forest and funnel plots. Nine studies were included in the meta-analysis, involving a total of 2,531 hemophilia A patients who were followed up from birth until death. A higher incidence of inhibitor development was found to be associated with recombinant FVIII (rFVIII) [odds ratio (OR)=1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)=1.89, 95% CI: 1.15-3.12]. The same trend was also found for high-responding inhibitors (OR=1.38, 95% CI: 0.70-2.70; HR=1.42, 95% CI: 0.84-2.39). rFVIII is associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived FVIII (pdFVIII).
PICO Summary
Population
Children and adults with haemophilia A (9 studies, n= 2,531).
Intervention
Plasma-derived factor VIII.
Comparison
Recombinant factor VIII.
Outcome
Most of the included participants in the studies were children. A higher incidence of inhibitor development was found to be associated with recombinant factor VIII (odds ratio (OR)= 1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)= 1.89, 95% CI: 1.15-3.12). The same trend was also found for high-responding inhibitors (OR= 1.38, 95% CI: 0.70-2.70; HR= 1.42, 95% CI: 0.84-2.39). Recombinant factor VIII was associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived factor VIII.
-
7.
Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis
Delgado-Flores CJ, García-Gomero D, Salvador-Salvador S, Montes-Alvis J, Herrera-Cunti C, Taype-Rondan A
PloS one. 2022;17(1):e0262273
-
-
-
Free full text
-
Editor's Choice
Abstract
BACKGROUND Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. OBJECTIVE To compare the effects of factor replacement therapies in patients with hemophilia. METHODS We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). RESULTS Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. CONCLUSIONS Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.
PICO Summary
Population
Patients with haemophilia (9 randomised controlled trials).
Intervention
Factor replacement therapy: prophylactic treatment.
Comparison
Other factor replacement therapies: episodic, tailored, or other therapies.
Outcome
Six studies compared episodic with prophylactic treatment in patients with haemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means (RM): 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups. Compared to the episodic treatment, the annualized joint bleeding rate was lower in the low-dose prophylactic treatment (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates, assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration.
-
8.
Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors
Pipe SW, Hermans C, Chitlur M, Carcao M, Castaman G, Davis JA, Ducore J, Dunn AL, Escobar M, Journeycake J, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2022
-
-
Free full text
-
Abstract
INTRODUCTION Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS Using a randomised crossover design, subjects received initial doses of 75 or 225 μg/kg eptacog beta followed by 75 μg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 μg/kg initial dose regimen (IDR) and 60% in the 225 μg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 μg/kg IDR and 98% for the 225 μg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION Both 75 and 225 μg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.
-
9.
Efficacy, safety and bioequivalence of the human-derived B-domain-deleted recombinant factor VIII TQG202 for prophylaxis in severe haemophilia A patients
Xi Y, Jin C, Liu W, Zhou H, Wang Z, Zhou R, Lou S, Zhao X, Chen F, Cheng P, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2022
-
-
Free full text
-
Abstract
INTRODUCTION Current treatment of severe haemophilia A includes prophylaxis with factor VIII (FVIII) replacement. The supply of plasma-derived FVIII is short in China. PURPOSE To evaluate the efficacy and safety of a new B-domain deleted (BDD) recombinant FVIII (TQG202) produced by human-derived cells for prophylaxis in severe haemophilia A patients and compare the bioequivalence with Xyntha. METHODS This multicentre, clinical trial consisted of an open-label, randomized, two-period cross-over trial assessing single-dose pharmacokinetics (PK), and a single-arm clinical trial evaluating the efficacy and safety of 24 weeks of TQG202 prophylaxis, and repeated PK were assessed after prophylaxis phase. The single-dose was 50 IU/kg in PK assessment, and the initial dose was 30 ± 5 IU/kg for prophylaxis. The primary endpoints of prophylaxis were the annualized bleeding rate (ABR) and the incremental recovery rate of the first administration. Adverse events (AEs) were recorded. RESULTS Twenty-six participants were enrolled in the PK assessment and 81 participants in the prophylaxis phase. Mean age was 25.9 ± 10.8 years and all participants were male. The results of PK assessment showed TQG202 is bioequivalent to Xyntha. The total ABR was 2.0 (95% CI: 1.2-2.9) in prophylaxis phase. The mean incremental recovery rate of the first administration was .027 (95% CI: .026-.028) (IU/ml)/(IU/kg). AEs occurred in 42 participants, with an incidence of 51.9%. One severe AE not related to TQG202 occurred. No participants developed FVIII inhibitors. CONCLUSION TQG202 shows bioequivalence with Xyntha. The promising efficacy and tolerability in the severe haemophilia A prophylaxis support the use of TQG202in clinical practice.
-
10.
Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study
Klamroth, R., Windyga, J., Radulescu, V., Collins, P. W., Stasyshyn, O., Ibrahim, H. M., Engl, W., Tangada, S. D., Savage, W., Ewenstein, B.
Blood. 2021;137(13):1818-1827
Abstract
Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.