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.
•Targeting 1% to 3% and 8% to 12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across arms.•Rurioctocog alfa pegol consumption varied widely in each arm with overlapping ranges, emphasizing the need for personalized treatment.
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Background: Fidanacogene elaparvovec (PF-06838435, formerly SPK-9001) is an adeno-associated virus (AAV)-based gene therapy designed to deliver a high-activity human factor IX (FIX) variant ...transgene, FIX-R338L, resulting in endogenous FIX production in people with hemophilia B. To date, 45 participants with moderately severe to severe (FIX:C ≤2%) hemophilia B have received fidanacogene elaparvovec as part of the ongoing phase 3 study, BENEGENE-2 (NCT03861273). Of these 45 participants, 6 returned to prophylaxis (RTP) of FIX after initially responding to treatment. We describe the characteristics of the RTP participants. Methods: Participants with baseline FIX activity ≤2% received a single dose of 5e11 vg/kg fidanacogene elaparvovec (AAVrh74 variant) as part of the phase 3 study (N=45). Participants suspended prophylaxis following vector infusion (1 participant continued for 2 weeks post infusion), which could be resumed per the investigator's discretion and the protocol provided guidance for when to consider resuming prophylaxis: ≥2 consecutive central laboratory FIX activity levels ≤2% at least 2 weeks apart and/or ≥2 spontaneous joints bleeds within 4 weeks and/or ≥3 spontaneous bleeds overall (joint and non-joint). Results: Prior to fidanacogene elaparvovec infusion, all 45 participants had completed at least 6 months of prophylaxis as part of the lead-in study (BENEGENE-1, NCT03587116). The mean age (range) of all 45 study participants was 33.2 y (18-62) and the 6 RTP participants had a mean age (range) of 28.3 y (18-47), of whom 4 were <30 y old. The region, race, and weight of the 6 RTP participants were representative of the entire study population (Table 1). All RTP participants initially responded to gene therapy and achieved peak FIX activity levels >5%, determined by one-stage actin-FSL (7-22.1%) and one-stage Synthasil (18.3-45.5%) across Days 36-97. Time to RTP from fidanacogene elaparvovec dose ranged from Days 155 to 623. The reasons reported for RTP were low FIX activity in 5 participants, of whom 1 had a prior history of intracerebral hemorrhage, and increased bleeds in 1 participant. Five participants recorded ≥1 bleeding event prior to resumption of prophylaxis. All RTP participants were treated with ≥1 course of corticosteroids for presumed cellular immune response. In all cases, maximum alanine aminotransferase was 1-2x upper limit of normal. Two RTP participants had an ELISPOT drawn within ±1 day of starting corticosteroids; both were negative for capsid peptides (Table 2). In comparison, 4 participants who took corticosteroids but did not resume prophylaxis were positive for capsid. All 6 RTP participants had a decline in FIX activity from peak levels in the absence of inhibitors, but displayed variable decline prior to and during corticosteroid treatment, or after completion of corticosteroid wean, with and without some elevation of liver enzyme at the time of the decline. Conclusion: The 6 RTP participants who received fidanacogene elaparvovec in the phase 3 study (BENEGENE-2) initially responded to therapy before a heterogenous decline in FIX activity. The limited number of participants and lack of consistent patterns and demographic features make identifying predictors of potential RTP challenging. Although all RTP participants were treated with corticosteroids during this study, not all participants treated with corticosteroids RTP of FIX. Predictors of loss of response have not been identified and further work is ongoing to potentially identify factors associated with increased risk of RTP.
Patients with hemophilia who have recurrent hemarthroses develop hemophilic arthropathy (HA). Regular prophylaxis with factor (F) VIII (FVIII) can reduce HA, but there is a need for objective outcome ...measures to evaluate treatment efficacy.
Evaluate and assess collagen turnover biomarkers in patients with hemophilia A to determine the efficacy of rurioctocog alfa pegol treatment and understand their potential as tools for guiding treatment decisions and monitoring outcomes.
Joint remodeling was assessed by analyzing serum levels of collagen remodeling products at baseline and months 3, 6, 9, and 12 in a 98 patient subset receiving pharmacokinetics-guided prophylaxis with rurioctocog alfa pegol, targeting FVIII trough levels of 1 to 3 International Units (IU)/dL or 8 to 12 IU/dL (PROPEL study, NCT0285960).
Basement membrane metabolism-related type 4 collagen remodeling products (C4M and PRO-C4) decreased after 3 months at all time points by up to 25% at 1 to 3 IU/dL (P = .049, P < .0001) and 8 to 12 IU/dL FVIII trough levels (P = .0002, P < .0001). Interstitial tissue metabolism-related type 3 (C3M) and 5 (PRO-C5) collagen remodeling products decreased after 3 months, by up to 19% at 1 to 3 IU/dL FVIII trough level (P = .0001, P = .009) and 23% at 8 to 12 IU/dL FVIII trough level (P = .0002, P = .001). An increase of up to 12% was seen for cartilage metabolism-related type 2 collagen product (PRO-C2, not C2M) after 6 months at both trough levels (P = .01, P = .005). When stratified by prior treatment, changes in C3M (P = .03) and C4M (P = .02) levels were observed between trough levels for prior on-demand treatment but not for prophylaxis prior to study entry.
Joint improvement measured by collagen remodeling biomarkers specific to the basement membrane, interstitial matrix, and cartilage was seen with pharmacokinetics-guided prophylaxis. These collagen remodeling biomarkers warrant further exploration as biomarkers to guide treatment toward improvement in HA.
Background
Recombinant porcine factor VIII (rpFVIII, OBI‐1, susoctocog alfa) is used for the treatment of acute bleeds in patients with acquired hemophilia A (AHA). Inhibitors in AHA can sometimes ...cross‐react with rpFVIII.
Objectives
To assess the frequency, strength, and determinants of cross‐reactivity.
Patients/methods
Baseline samples from 70 patients of the prospective, observational cohort study GTH‐AH 01/2010 were assessed for anti‐human FVIII and anti‐rpFVIII inhibitors using modified Nijmegen‐Bethesda assays, as well as anti‐human FVIII domain reactivity using enzyme‐linked immunoassay (ELISA).
Results
Anti‐human FVIII inhibitors were present in all samples ranging between 0.7 and 3891 Bethesda Units (BU)/mL. Inhibitors from 31 of 70 patients (44%) partially inhibited rpFVIII with anti‐rpFVIII titers ranging between 0.5 and 471 BU/mL. Anti‐rpFVIII titers were ≤5 BU in most patients. Patients with cross‐reacting inhibitors, as compared to patients without, had significantly higher anti‐human FVIII titers (27.8 versus 5.4 BU/mL) and lower baseline FVIII activity (<1 versus 2.6 IU/dL). The ratio between anti‐rpFVIII to anti‐human titers was highest for inhibitors involving the C1 domain. Cross‐reactivity was very rare, if inhibitors reacted only with the C2 domain of FVIII (6%). An anti‐human FVIII titer of >100 BU/mL predicted cross‐reactivity with 97% likelihood, whereas an anti‐human FVIII titer of <3.8 BU/mL predicted absent cross‐reactivity with 90% likelihood.
Conclusion
Cross‐reacting inhibitors should be considered when choosing a treatment for bleeding patients with AHA. Cross‐reactivity is frequent in patients with anti‐human FVIII titers of >100 BU/mL.
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Introduction: The ongoing German Antihemophilic factor (recombinant) (rAHF) Hemophilia A (HA) outcome Database (AHEAD) study (DRKS00000556) evaluates the real-world, long-term effectiveness and ...safety of rAHF (Advate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) and rurioctocog alfa pegol (Adynovi®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in patients with HA treated in routine clinical practice. The objective of this analysis was to describe the hemostatic effectiveness of rurioctocog alfa pegol administered as standard prophylaxis (SP) and individualized pharmacokinetic-guided prophylaxis (PKP) in adult patients (≥18 years of age) with severe HA (factor VIII activity ˂1%).
Methods: The German AHEAD study is a non-interventional, prospective, multicenter study. This analysis focused on patients switched from rAHF to rurioctocog alfa pegol or enrolled on rurioctocog alfa pegol during 7 years of follow-up (data cutoff: Jun 30, 2020), using a time-free method of analysis to provide average values for each outcome per patient per treatment year, irrespective of the duration of study follow-up. Key outcomes included annualized bleeding rates (ABRs all bleeds), annualized joint bleeding rates (AJBRs), factor consumption, and factor VIII trough levels expressed in patient-years. Adverse events were also reported. In the analyses presented for bleeding rates and consumption, the switch year was excluded. These results focus on rurioctocog alfa pegol; however, outcomes for rAHF are included in the table for comparison. This study was reviewed/approved by the relevant institutional review boards/ethics committees of all participating centers.
Results: A total of 382 patients were receiving rAHF at baseline; 60 of these switched from rAHF to rurioctocog alfa pegol during the study. Two additional patients were enrolled on rurioctocog alfa pegol, giving a total of 62 patients in the rurioctocog alfa pegol group (severe HA, n=55; moderate HA, n=7; PKP, n=27; SP, n=35). Median age (range) for the 322 patients who received rAHF throughout the study (severe HA, n=258; moderate HA, n=64) was 24 (1-80) years. In the time-free analysis of bleeding rates, the combined rurioctocog alfa pegol data for enrolled patients and switched patients with severe HA resulted in a total of 23 patient-years of data for rurioctocog alfa pegol (SP, n=8 patient-years; PKP, n=15 patient-years). Median (Q1-Q3) ABRs were lower in patients receiving PKP with rurioctocog alfa pegol vs SP (0 0-2.9 vs 0.5 0-1.6). Similar median AJBRs were observed between the PKP and SP groups (Table). A higher proportion of patients receiving PKP vs SP had an ABR or AJBR of zero (ABRs, 60% vs 50%; AJBRs, 80% vs 75%, respectively). Mean annualized total dose for rurioctocog alfa pegol was 4154 IU/kg for SP and 4662 IU/kg for PKP. Mean (median Q1-Q3) target FVIII trough levels for patients with severe HA receiving rurioctocog alfa pegol PKP were 6.0% (5.0% 3.2%-7.9%). For patients receiving rAHF PKP, the mean (median Q1-Q3) target trough levels were 3.5% (3.0% 2.0%-5.0%). Adverse events occurred in 9/62 (14.5%) patients treated with rurioctocog alfa pegol in the time-free analysis; 4 (6.5%) were serious adverse events and none were treatment related. De novo inhibitors were reported for 3 patients in the rAHF group and for none in the rurioctocog alfa pegol group.
Conclusion: These real-world data showed lower bleeding rates with rurioctocog alfa pegol PKP versus SP in the time-free analysis.
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Klamroth: Daiichi Sankyo: Other, Speakers Bureau; LEO: Other, Research Funding, Speakers Bureau; Uniqure: Consultancy, Other; Sobi: Consultancy, Other, Speakers Bureau; Sanofi: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Octapharma: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Roche/Cugai: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Biotest: Consultancy, Other: Travel support, Speakers Bureau; BioMarin: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Shire (a Takeda company): Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Pfizer: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Grifols: Speakers Bureau. Kurnik: Bayer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Shire (a Takeda company): Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Research Funding; Biotest: Consultancy, Speakers Bureau. Wenning: Bayer: Research Funding; Biotest: Consultancy, Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Shire (a Takeda company): Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Escuriola-Ettingshausen: Biotest: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Shire (a Takeda company): Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy; Grifols: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Roche/Chugai: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; Kedrion: Speakers Bureau; Pfizer: Speakers Bureau. Regensburger: Takeda Pharma Vertrieb GmbH & Co. KG: Current Employment. Tang: Takeda Pharmaceuticals International AG: Current Employment; Takeda: Current equity holder in publicly-traded company. Gu: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Guerra: Takeda Pharmaceuticals: Current Employment; Takeda: Current equity holder in publicly-traded company. Oldenburg: Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Freeline: Consultancy, Honoraria, Speakers Bureau; Grifols: Consultancy, Honoraria, Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL-Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Speakers Bureau; Biotest: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen Idec: Consultancy, Honoraria, Speakers Bureau; University Clinic Bonn AöR: Current Employment; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire (a Takeda company): Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau.
Introduction
Adeno‐associated virus (AAV)‐based gene therapy for haemophilia presents a challenge to the existing structure of haemophilia centres and requires a rethink of current collaboration and ...information exchange with the aim of ensuring a system that is fit‐for‐purpose for advanced therapies to maximise benefits and minimise risks. In Europe, a certification process based on the number of patients and facilities is offered to the haemophilia centres by European Haemophilia Network (EUHANET).
Aim and methods
This joint European Association for Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) publication describes criteria for centres participating in gene therapy care that require a reassessment of the infrastructure of comprehensive care and provides an outlook on how these criteria can be implemented in the future work of haemophilia centres.
Results
The core definition of a haemophilia treatment centre remains, but additional roles could be implemented. A modifiable ‘hub‐and‐spoke’ model addresses all aspects associated with gene therapy, including preparation and administration of the gene therapy product, determination of coagulation and immunological parameters, joint score and function, and liver health. This will also include the strategy on how to follow‐up patients for a long‐term safety and efficacy surveillance.
Conclusion
We propose a modifiable, networked ‘hub and spoke’ model with a long term safety and efficacy surveillance system. This approach will be progressively developed with the goal of making haemophilia centres better qualified to deliver gene therapy and to make gene therapy accessible to all persons with haemophilia, irrespective of their country or centre of origin.
Background
The current standard of care for patients with hemophilia A is regular prophylaxis with factor VIII (FVIII) administered intravenously. Interest in subcutaneous (s.c.) administration, to ...potentially increase convenience, reduce the treatment burden and improve compliance, is increasing.
Objectives
Evaluate the pharmacokinetics (PK), immunogenicity, safety, and preliminary efficacy of s.c. administration of turoctocog alfa pegol (s.c. N8‐GP) in adult or adolescent previously treated patients (PTPs) with severe hemophilia A (alleviate 1; NCT02994407).
Patients/Methods
In part A, 24 PTPs received a single dose of s.c. N8‐GP (12.5, 25, 50, or 100 IU/kg) with 6 patients per cohort. PK modelling of data from part A supported a suitable dose for part B. Part B comprised a multiple dose trial in 26 PTPs; patients <60 kg received 2000 IU and patients ≥60 kg received 4000 IU s.c. N8‐GP daily for 3 months.
Results
Single‐dose s.c. N8‐GP supported dose linearity. Daily prophylaxis with s.c. N8‐GP appeared well tolerated and efficacious, achieving a mean trough FVIII activity close to 10% at steady state. Five patients developed anti‐N8‐GP binding antibodies after 42 to 91 exposure days, one of whom developed an inhibitor to FVIII. Anti‐N8‐GP antibody appearance was associated with a decline in FVIII plasma activity in four of the five patients. Five patients reported a total of nine treatment‐requiring bleeding episodes during prophylaxis.
Conclusions
Subcutaneous administration of N8‐GP is associated with a high incidence of antibodies in PTPs with severe hemophilia A. Further clinical development of s.c. N8‐GP has been suspended.
Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients ...with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT.
Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of ...bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.
Standard treatment of haemophilia A is based on replacing the missing coagulation factor VIII (FVIII) to treat and prevent bleeding episodes. The most challenging complication of FVIII therapy is the ...development of neutralizing antibodies (inhibitors) that can render treatment ineffective. Eradication of the inhibitor through immune tolerance induction (ITI) remains the most effective strategy for managing these patients. Bypassing agents can be used to help restore haemostasis in inhibitor patients. Several novel agents have recently been developed, such as the FVIII mimetic agent emicizumab, which has been effective in reducing the annualized bleeding rate in haemophilia A patients with inhibitors. When coadministered with repetitive high doses of activated prothrombin complex concentrate (ie >100 U/kg/d for ≥24 hours), emicizumab was associated with thrombotic microangiopathy and thrombosis events. As a consequence the United Kingdom Haemophilia Centres Doctors' Organisation (UKHCDO) issued the first guidance on the treatment of bleeding episodes in patients receiving emicizumab. To build on and extend this work, a panel of German haemophilia specialists met to discuss the UK guidance, review current evidence and provide additional guidance for German healthcare professionals on how to optimize the management of patients with haemophilia A receiving emicizumab. Recommendations are provided on the use of bypassing and other agents to manage breakthrough bleeding, ITI in the emicizumab era, haemostatic support during surgery and issues relating to laboratory monitoring.
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