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Factor VIII Activity. The one-stage clotting assay data shown represent means and standard errors of the mean.
Source publication
Introduction:
Primary factor VIII (FVIII) prophylaxis is the optimal treatment in children with severe haemophilia A. They are expected to benefit from extended half-life (T1/2 ) FVIII coverage by reduced infusion frequency while maintaining haemostatic efficacy.
Aims:
To determine immunogenicity, pharmacokinetics (PK), efficacy, safety and qual...
Context in source publication
Context 1
... 855 demonstrated an extended PK profile com- pared to ADVATE at the same (60 AE 5 IU kg À1 ) dose level (Fig. 2). Increases in T 1/2 MRT and AUC com- pared to ADVATE were similar in the younger and older cohorts (Table 4). Depending on the PK model and FVIII assay (one-stage clotting or chromogenic substrate) used, T 1/2 and MRT increased by 1.3-to 1.5-fold, AUC by 1.2-to 1.8-fold and CL decreased by 0.5-to 0.8-fold compared to ADVATE (Table ...
Similar publications
IntroductionProphylaxis with recombinant factor VIII (rFVIII) is the current standard of care for haemophilia A. Several approaches have been used to extend the half-life of rFVIII to improve prophylaxis outcomes. An indirect comparison of pivotal clinical trial data was performed to evaluate the relative efficacy of two extended half-life therapie...
Although the use of prophylaxis regimens with prolonged half-life factors is now widespread in the world of hemophilia A, there is a lack of real-life evidence on the impact of these products on joint health, adherence, and quality of life of patients. Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-l...
Introduction:
As standard care of severe haemophilia A (SHA), prophylaxis should be individualised.
Aim:
This study aimed to investigate the effectiveness of this new-proposed individualised prophylaxis protocol.
Methods:
Boys with SHA were enrolled and followed a PK-guided, trough-level escalating protocol of prophylaxis after a six-month obs...
With licensure of extended half‐life (EHL) factor products and the changing landscape of available hemophilia products, patients and providers have options for less treatment‐intense prophylaxis. The impact of these products in clinical practice to date remains understudied.
We aimed to quantify the use of EHL products in prophylaxis in the US usin...
Anti-drug antibody (ADA) development is a significant complication in the treatment of several conditions. For decades, the mainstay of hemophilia A treatment was the replacement of deficient coagulation factor VIII (FVIII) to restore hemostasis, control, and prevent bleeding events. Recently, new products have emerged for hemophilia A replacement...
Citations
... 25,32,33 Most of the amine residues are located at the surface of the FVIII molecule, mainly within the B-domain. 25 Compared with octocog alfa, the mean half-life of rurioctocog alfa pegol is 1.3-to 1.5-fold longer in children aged <12 years with severe hemophilia A, and 1.4-to 1.5fold longer in patients aged ≥12 years with severe hemophilia A. 25,34 Rurioctocog alfa pegol has been shown to be effective and well tolerated in the prevention and control of bleeding events in PTPs with severe hemophilia A. 25,[34][35][36][37] In this article, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol in patients with severe hemophilia A who had previously received treatment with either plasma-derived or recombinant FVIII for ≥50 EDs (patients aged <6 years) or ≥150 EDs (patients aged ≥6 years) without FVIII inhibitors. 25,[34][35][36][37] The immunogenicity data include FVIII inhibitors as well as IgM and IgG antibodies binding to PEG-FVIII, FVIII, or PEG. ...
... 25,32,33 Most of the amine residues are located at the surface of the FVIII molecule, mainly within the B-domain. 25 Compared with octocog alfa, the mean half-life of rurioctocog alfa pegol is 1.3-to 1.5-fold longer in children aged <12 years with severe hemophilia A, and 1.4-to 1.5fold longer in patients aged ≥12 years with severe hemophilia A. 25,34 Rurioctocog alfa pegol has been shown to be effective and well tolerated in the prevention and control of bleeding events in PTPs with severe hemophilia A. 25,[34][35][36][37] In this article, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol in patients with severe hemophilia A who had previously received treatment with either plasma-derived or recombinant FVIII for ≥50 EDs (patients aged <6 years) or ≥150 EDs (patients aged ≥6 years) without FVIII inhibitors. 25,[34][35][36][37] The immunogenicity data include FVIII inhibitors as well as IgM and IgG antibodies binding to PEG-FVIII, FVIII, or PEG. ...
... 25 Compared with octocog alfa, the mean half-life of rurioctocog alfa pegol is 1.3-to 1.5-fold longer in children aged <12 years with severe hemophilia A, and 1.4-to 1.5fold longer in patients aged ≥12 years with severe hemophilia A. 25,34 Rurioctocog alfa pegol has been shown to be effective and well tolerated in the prevention and control of bleeding events in PTPs with severe hemophilia A. 25,[34][35][36][37] In this article, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol in patients with severe hemophilia A who had previously received treatment with either plasma-derived or recombinant FVIII for ≥50 EDs (patients aged <6 years) or ≥150 EDs (patients aged ≥6 years) without FVIII inhibitors. 25,[34][35][36][37] The immunogenicity data include FVIII inhibitors as well as IgM and IgG antibodies binding to PEG-FVIII, FVIII, or PEG. Additionally, we analyzed antibodies against a total protein preparation of CHO host cells, which are used for the expression of octocog alfa, the source material for rurioctocog alfa pegol. ...
Rurioctocog alfa pegol is an extended half-life full-length recombinant factor VIII (FVIII) bound to 20 kDa polyethylene glycol (PEG) that has been shown to be well tolerated and efficacious in the treatment and prevention of bleeding events in previously treated patients with severe hemophilia A. Here, we present a comprehensive analysis of immunogenicity data collected during 6 clinical studies of rurioctocog alfa pegol including a total of 360 unique previously treated patients with severe hemophilia A. The analysis included treatment-emerging FVIII neutralizing antibodies (FVIII inhibitors), pre-existing and treatment-emerging antibodies binding to FVIII, PEG-FVIII, or PEG, and treatment-emerging antibodies binding to Chinese hamster ovary host cell proteins. Moreover, the potential association between the presence of these binding antibodies and adverse events (AEs) observed in patients was investigated and the potential impact of these antibodies on the incremental recovery of rurioctocog alfa pegol in patients was analyzed. Overall, the data indicate that rurioctocog alfa pegol is not associated with any unexpected immunogenicity characteristics. One of the 360 patients developed a transient FVIII inhibitor with a titer of 0.6 BU/mL, which was not associated with any serious AEs. Antibodies binding to FVIII, PEG-FVIII, or PEG were not detected at the time when the inhibitor was present. Moreover, 54 of the 360 patients either entered the clinical studies with pre-existing binding antibodies or developed these antibodies after exposure to rurioctocog alfa pegol. These antibodies were transient in most patients and did not show any causal relationship to either AEs or spontaneous bleeding episodes.
... Prophylactic and on-demand administration have been shown to be effective for the prevention and treatment of bleeding episodes, including during surgery, in patients with moderately severe or severe hemophilia A. [8][9][10][11] Rurioctocog alfa pegol was designed to extend the half-life of octocog alfa by including a covalently conjugated polyethylene glycol polymer. Clinical data have demonstrated equivalent efficacy and safety of rurioctocog alfa pegol in previously treated patients with hemophilia A. [12][13][14] However, real-world data examining the long-term outcomes of FVIII replacement, including the impact on joint health and patient QoL, are limited. Therefore, the international, observational Antihemophilic Factor (recombinant rAHF) Hemophilia A Outcome Database (AHEAD) study was established to evaluate the effectiveness and safety of FVIII replacement in patients with hemophilia A receiving octocog alfa or rurioctocog alfa pegol from 22 countries. ...
Background
Real-world data assessing treatment outcomes in patients with hemophilia A in routine clinical practice are limited.
Objective
To evaluate the effectiveness and safety of octocog alfa in patients with moderate/severe hemophilia A receiving treatment in clinical practice.
Design
The international Antihemophilic Factor Hemophilia A Outcome Database study is an observational, noninterventional, prospective, multicenter study.
Methods
This planned interim data read-out was conducted following 7 years of observation of patients receiving octocog alfa (cut-off, 30 June 2020). The primary endpoint was joint health status, assessed by the Gilbert Score. Secondary endpoints included annualized bleeding rates (ABRs), Hemophilia Joint Health Score (HJHS), health-related quality of life, consumption, and safety. This post hoc analysis stratified data by hemophilia severity at baseline [moderate, factor VIII (FVIII) 1–5%; severe, FVIII <1%].
Results
Of the 711 patients in this analysis, 582 (82%) were receiving prophylaxis with octocog alfa at enrollment, and 498 (70%) had severe disease. Median Gilbert Scores were higher with on-demand therapy versus prophylaxis and scores were comparable in moderate and severe disease. In patients receiving prophylaxis, there was an improvement in HJHS Global Gait Score over 7 years of follow-up overall and in patients with severe disease. ABRs and annualized joint bleeding rates were low across all 7 years. An ABR of zero was reported in 34–56% of prophylaxis patients versus 20–40% in the on-demand group. ABRs were similar in severe and moderate disease. In total, 13/702 (1.9%) patients experienced 18 treatment-related adverse events.
Conclusion
These data demonstrate the long-term effectiveness and safety of octocog alfa in patients with moderate and severe hemophilia A, especially in those receiving prophylaxis. The high number of patients receiving on-demand treatment experiencing zero bleeds could be due to selection bias within the study, with patients with less severe disease more likely to be receiving on-demand treatment.
Trial registration
ClinicalTrials.gov: NCT02078427.
... [5][6][7] Rurioctocog alfa pegol (Adynovate ® [US]/Adynov ® [Europe]; Takeda Pharmaceuticals U.S.A, Inc., Lexington, MA, USA) is an extended t 1/2 recombinant FVIII. It is approved for routine prophylaxis in children and adults in the United States and patients ⩾12 years of age in Europe with hemophilia A. 8,9 Clinical data have demonstrated the efficacy and safety of rurioctocog alfa pegol targeting FVIII trough levels ⩾1% in previously treated patients with hemophilia A. [10][11][12] The recommended dose and infusion frequency for routine rurioctocog alfa pegol prophylaxis is a fixed dose of 40-50 IU/kg twice weekly in patients ⩾12 years of age, and 40-60 IU/kg twice weekly in patients <12 years of age. 8,9 This reduces the infusion-related treatment burden compared with standard t 1/2 products. ...
... The efficacy and safety of using a fixed-dose regimen of rurioctocog alfa pegol in patients with severe hemophilia A has previously been demonstrated in various clinical studies. 10,11,17 However, fixed-dose regimens do not account for the substantial interpatient variability in FVIII t 1/2 . Data on the benefits of targeting a FVIII trough level >1-3%, using PK-guided prophylaxis to personalize treatment, are limited and have previously relied on data derived from modeling. ...
Background
The phase 3, prospective PROPEL study demonstrated that pharmacokinetic (PK)-guided prophylaxis targeting elevated factor VIII (FVIII) troughs in patients with hemophilia A resulted in lower annualized bleeding rates (ABRs) and a higher proportion of patients experiencing zero bleeds in the second 6 months of treatment when targeting a FVIII trough of 8–12% versus 1–3%.
Objective
To investigate the benefit of PK-guided prophylaxis with rurioctocog alfa pegol targeting two FVIII trough levels in specific patient subgroups in a post hoc analysis using data from PROPEL.
Design
This is a post hoc analysis of data from the PROPEL study. The design and primary outcomes of the prospective, randomized PROPEL study (NCT02585960) have been reported previously.
Methods
This post hoc analysis reports data stratified by FVIII half-life ( t 1/2 ), hemophilic arthropathy status, number of target joints at screening, previous treatment regimen, and ABR range in the 12 months before study entry.
Results
Targeting an elevated FVIII trough of 8–12% was associated with higher average FVIII levels over time, regardless of FVIII t 1/2 at baseline. The decrease in total ABR between the 8–12% and 1–3% arms was greatest in patients with a FVIII t 1/2 of 6 to <12 h (0.7 versus 3.5); a higher number of target joints, that is, at least four target joints, at baseline (0.2 versus 1.6); the presence of arthropathy (0.1 versus 1.7); and those previously treated on-demand (0.3 versus 1.8).
Conclusion
These results support the feasibility of targeting elevated FVIII levels using personalized rurioctocog alfa pegol prophylaxis. These benefits may be especially important in patients with a short FVIII t 1/2 and those receiving standard prophylaxis with frequent breakthrough bleeds, arthropathy, and target joints.
Registration
ClinicalTrials.gov Identifier: NCT02585960; https://clinicaltrials.gov/ct2/show/NCT02585960
... Within the treatments with rFVIII EHL, good outcomes were obtained with pegylated recombinant factors: in pediatric patients, rurioctocog alfa pegol allowed the frequency of infusions to be reduced to two days a week [52], and sometimes using damoctocog alfa pegol at a dose of 50 ± 10 IU/kg once every 5 days reduced the frequency of hemarthrosis [53]. Since the introduction of the new FVIII monoclonal purified or recombinant concentrates, great attention has been focused on the pharmacokinetic profile [54,55]. ...
The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery using continuous infusion (CI) versus bolus injection (BI) of standard and extended half-life Factor VIII (FVIII) concentrates in severe hemophilia A patients. Among the side effects, the risk of development of neutralizing antibodies (inhibitors) and thromboembolic complications was addressed. The specific needs of mild hemophilia A patients were described, as well as the usage of bypassing agents to treat patients with high-responding inhibitors. Young hemophilia A patients may take significant advantages from primary prophylaxis three times or twice weekly, even with standard half-life (SHL) rFVIII concentrates. Patients affected by severe hemophilia B probably have a less severe clinical phenotype than severe hemophilia A patients, and in about 30% of cases may undergo weekly prophylaxis with an rFIX SHL concentrate. The prevalence of missense mutations in 55% of severe hemophilia B patients allows the synthesis of a partially changed FIX molecule that can play some hemostatic role at the level of endothelial cells or the subendothelial matrix. The flow back of infused rFIX from the extravascular to the plasma compartment allows a very long half-life of about 30 h in some hemophilia B patients. Once weekly, prophylaxis can assure a superior quality of life in a large severe or moderate hemophilia B population. According to the Italian registry of surgery, hemophilia B patients undergo joint replacement by arthroplasty less frequently than hemophilia A patients. Finally, the relationships between FVIII/IX genotypes and the pharmacokinetics of clotting factor concentrates have been investigated.
... Prevalence and safety concerns regarding PEG accumulation and the formation of ADAs have been addressed in pre and post-approval clinical studies [35][36][37][38]. ...
Background:
The standard therapy for hemophilia A (HA) patients is the replacement with Factor VIII (FVIII) therapeutics. To overcome the limitation of the short half-life of wild-type FVIII protein, polyethylene glycol (PEG) can be coupled to therapeutic FVIII to improve pharmacokinetics.
Objectives:
To characterize antibodies developed against a FVIII therapeutic PEGylated with a 40 kDa PEG (40PEG-BDDFVIII) in two mild HA patients.
Methods:
An in-house bead-based immunoassay was developed to characterize and confirm the specificity of detected antibodies. The neutralizing nature of the antibodies towards PEGylated therapeutics was determined by a modified Nijmegen Bethesda Assay (NBA).
Results:
Two out of 46 patients treated with 40PEG-BDDFVIII developed inhibitory antibodies towards the drug. Switching to a non-PEGylated FVIII successfully increased the FVIII activity in both patients. In Patient 1, antibodies were raised against FVIII and PEG. Anti-FVIII antibodies were of IgG isotype, whereas anti-PEG antibodies were of IgG, IgM, and IgA isotype. In Patient 2, antibodies of IgG and IgA isotype were directed only against the PEG moiety. Competitive assays confirmed the specificity of the antibodies against PEG. The applied NBA revealed that patients anti-PEG antibodies and AGP3, an antibody against the backbone of PEG, can inhibit all currently available PEGylated therapeutics but to different degrees. No inhibitory FVIII antibodies were detected.
Conclusion:
Antibodies against the PEG moiety of 40PEG-BDDFVIII abolished the efficacy of the drug. This is the first report on real-world experiences with the development of neutralizing anti-PEG antibodies after treatment with PEGylated FVIII therapeutic in mild HA.
... It is indicated for on-demand treatment and routine prophylaxis [40-55 IU/kg body weight, twice weekly (BIW)], adjusted per clinical response [3]. Efficacy of rurioctocog alfa pegol for prophylaxis was demonstrated in open-label, phase II/III clinical trials, in which 38-40% of patients with severe HA had no bleeding episodes over 6 months with BIW prophylaxis [4,5]. Among previously treated patients aged 12-65 years, the median annualized bleed rate (ABR) was 1.9 versus 41.5 for patients treated on demand [4]. ...
Background
FVIII replacement is standard treatment for hemophilia A without inhibitors, but non-factor therapies, such as emicizumab, are changing the treatment landscape. We explore the ramifications of switching treatment.
Methods
Pharmacy database data (July 2017–May 2020) from patients with hemophilia A without inhibitors who switched to rurioctocog alfa pegol or emicizumab prophylaxis after ≥6 months’ prophylaxis with another FVIII product were analyzed for total mean weekly consumption, dosing frequency, product wastage, and ABR.
Results
Post-switch mean weekly consumption of prophylactic rurioctocog alfa pegol and emicizumab were 6224 IU/kg and 109 mg, respectively. Dosing schedules for emicizumab were primarily weekly (48.2%) and every 2 weeks (40.0%). Most patients in the rurioctocog alfa pegol cohort received treatment twice-weekly (83.3%). Mean product wastage of emicizumab (8.4%) was significantly higher versus rurioctocog alfa pegol (−0.3%; P < 0.001). Mean annualized emicizumab and rurioctocog alfa pegol wastage during prophylaxis was 330.82 mg and −974.80 IU, respectively. ABR change was not significantly different (P = 0.527) for patients switching to emicizumab (−1.05) or rurioctocog alfa pegol (−1.53).
Conclusions
Bleed rates were similar for patients receiving prophylaxis with emicizumab or rurioctocog alfa pegol after switching from prophylaxis with another FVIII. However, wastage associated with dispensing inaccuracies was greater with emicizumab.
... The formation of anti-PEG has been observed in previously conventionally treated HA patients substituted with pegylated EHL-FVIII concentrates. [93][94][95][96] While in the majority of cases, these antibodies did not affect FVIII function, also loss of treatment efficacy was observed. 96 In these cases, the antibodies were directed against the PEG moiety, specific for the EHL-FVIII molecule and did not cross-react with unmodified FVIII. ...
Haemophilia A (HA) and B (HB) are X-linked hereditary bleeding disorders caused by lack of activity of coagulation factors VIII (FVIII) or IX (FIX), respectively. Besides conventional products, modern replacement therapies include FVIII or FIX concentrates with an extended half-life (EHL-FVIII/FIX). Two main strategies for measuring plasma FVIII or FIX activity are applied: the one-stage clotting assay (OSCA) and the chromogenic substrate assay (CSA), both calibrated against plasma (FVIII/FIX) standards. Due to the structural modifications of EHL-FVIII/FIX, reagent-dependent assay discrepancies have been described when measuring the activity of these molecules. Assay discrepancies have also been observed in FVIII/FIX gene therapy approaches. On the other hand, nonfactor replacement by the bispecific antibody emicizumab, a FVIIIa-mimicking molecule, artificially shortens activated partial thromboplastin time-based clotting times, making standard OSCAs inapplicable for analysis of samples from patients treated with this drug. In this review, we aim to give an overview on both, the currently applied and future therapies in HA and HB with or without inhibitors and corresponding test systems suitable for accompanying diagnostics.
... 8 This modification also prolongs the half-life of rFVIII by 1.4-1.5 folds the original rFVIII, thereby reducing the administration frequency and maintaining better bleeding hemostasis of the hemophilic patients. 8, 9 The administration of rurioctocog alfa pegol increases the prevalence of zero-bleeding events in hemophilia A patients due to its lower future coagulation factor consumption after injection compared to the standard regimens. Hence, the use of this drug could offer potential advantages and might improve treatment adherence. ...
... Twenty-three were fully reviewed based on the eligibility criteria and 19 of these were excluded due to: (1) studies with a sub-analysis of other included studies (n = 2); (2) not reporting the outcome of interest (n = 7); or (3) conference abstracts (n = 10). Finally, four clinical trials 5,7,9,15 were included in the qualitative and quantitative synthesis. The overall study selection process is illustrated in Figure 1. ...
... Table 1 provides a summary of the studies included in the systematic review. The four uncontrolled clinical trials 5,7,9,15 included a total of 517 previously treated severe hemophilia A patients for prophylactic treatment, with the overall mean AE SD age of 23.9 AE 14.8. Only two studies by Mullins et al. 9 and Chowdary et al. 7 included a female patient. ...
Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A.
Methods : This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales.
Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety.
Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.
... Several PEGylated rFVIII products, such as rurioctocog alfa pegol, are currently in clinical use. Rurioctocog alfa pegol manifested a 1.4-to 1.6-fold prolongation in half-life when compared to standard rFVIII [20][21][22][23][24][25]. PEGylated rFIX, nonacog beta pegol, is also in clinical use, with a fivefold increase in half-life over standard rFIX [26], as well as being well tolerated with mostly mild/moderate adverse events (AEs), no inhibitor development, and a reduction in ABRs [27]. ...
Mainstay haemophilia treatment, namely intravenous factor replacement, poses several clinical challenges including frequent injections due to the short half-life of recombinant factors, intravenous administration (which is particularly challenging in those with difficult venous access), and the risk of inhibitor development. These impact negatively upon quality of life and treatment compliance, highlighting the need for improved therapies. Several novel pharmacological therapies developed for haemophilia aim to rebalance the clotting cascade and potentially circumvent the aforementioned challenges. These therapies utilise a range of different mechanisms, namely: the extension of the circulating half-life of standard recombinant factors; the mimicking of factor VIII cofactor activity; rebalancing of coagulation through targeting of natural anticoagulants such as antithrombin and tissue factor pathway inhibitor; and inducing the production of endogenous factors with gene therapy. These therapies carry the potential of revolutionising haemophilia treatment by alleviating the current challenges presented by mainstay factor replacement. This review will provide an overview of the key trial findings related to novel therapies based on the mechanisms described above.
... 8 This modification prolongs the half-life of rFVIII by 1.4-1.5 folds the original rFVIII, thereby reducing the administration frequency and maintaining better bleeding hemostasis of the hemophilic patients. 8,9 Yet, to the best of our knowledge, there are no pooled studies assessing the efficacy, safety, and immunogenicity of rurioctocog alfa pegol. Therefore, here, we aim to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol, a newly-developed prophylactic agent, in previously treated patients with severe hemophilia A. ...
... Twenty-three were fully reviewed based on the eligibility criteria and 19 of these were excluded due to: (1) studies with a sub-analysis of other included studies (n = 2); (2) not reporting the outcome of interest (n = 7); or (3) conference abstracts (n = 10). Finally, four clinical trials 5,7,9,15 were included in the qualitative and quantitative synthesis. The overall study selection process is illustrated in Figure 1. ...
... Table 1 provides a summary of the studies included in the systematic review. The four uncontrolled clinical trials 5,7,9,15 included a total of 517 previously treated severe hemophilia A patients for prophylactic treatment, with the overall mean AE SD age of 23.9 AE 14.8. Only two studies by Mullins et al. 9 and Chowdary et al. 7 included a female patient. ...
Background: Patients with severe hemophilia often present with painful joint and soft tissue bleeding which may restrict them from their daily activities. The current standard of care still relies on a regular prophylactic factor VIII (FVIII), which has a high daily treatment burden. Recently, rurioctocog alfa pegol, a third-generation recombinant FVIII with a modification in its polyethylene glycol (PEG) component, has been developed. Several trials have studied this synthetic drug as bleeding prophylaxis in severe hemophilia A. This study aims to evaluate the efficacy, safety, and immunogenicity of rurioctocog alfa pegol for previously treated patients with severe hemophilia A.
Methods : This study was conducted in conformity with the PRISMA guidelines. Data were retrieved from PubMed, Scopus, Cochrane Library, Wiley Online Library, and CINAHL (via EBSCOhost). Study qualities were assessed using the Methodological Index for Non-Randomized Studies (MINORS) and Modified Jadad scales.
Results: Four studies involving 517 previously treated severe hemophilia A patients were included in this study. The pooled mean of total annualized bleeding rate (ABR) and hemostatic efficacy was 2.59 (95% CI = 2.04–3.14) and 92% (95% CI = 85%–97%), respectively. Only 30 (2.3%) non-serious and one (1.4%) serious adverse events were considered related to rurioctocog alfa pegol treatment. At the end of the studies, no development of FVIII inhibitory antibodies was observed. None of the developed binding antibodies to FVIII, PEG-FVIII, or PEG was correlated to the treatment efficacy and safety.
Conclusions: Despite the limited availability of direct comparison studies, our analyses indicate that rurioctocog alfa pegol could serve as a safe and effective alternative for bleeding prophylaxis in previously treated hemophilia A patients. Moreover, it appears to have low immunogenicity, which further increases the safety profile of the drug in such clinical conditions.
