This multinational, randomized, single-blind trial investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously ...treated patients with hemophilia B (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to either 10 IU/kg or 40 IU/kg once weekly or to on-demand treatment of 28 weeks. No patients developed inhibitors, and no safety concerns were identified. Three hundred forty-five bleeding episodes were treated, with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis group, 2.93 in the 10 IU/kg prophylaxis group, and 15.58 in the on-demand treatment group. In the 40 IU/kg group, 10 (66.7%) of 15 patients experienced no bleeding episodes into target joints compared with 1 (7.7%) of 13 patients in the 10 IU/kg group. Health-related quality of life (HR-QoL) assessed with the EuroQoL-5 Dimensions visual analog scale score improved from a median of 75 to 90 in the 40 IU/kg prophylaxis group. Nonacog beta pegol was well tolerated and efficacious for the treatment of bleeding episodes and was associated with low ABRs in patients receiving prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL. This trial was registered at www.clinicaltrials.gov as #NCT01333111.
•Nonacog beta pegol, a recombinant glycoPEGylated FIX with extended half-life, was developed to improve care for patients with hemophilia B.•Weekly prophylaxis with nonacog beta pegol was well tolerated and was associated with low bleeding rates and an improved quality of life.
Introduction
Structural and chemical modifications of factor VIII (FVIII) products may influence their behaviour in FVIII activity assays. Hence, it is important to assess the performance of FVIII ...products in these assays. Efanesoctocog alfa is a new class of FVIII replacement therapy designed to provide both high sustained factor activity levels and prolonged plasma half‐life.
Aim
Evaluate the accuracy of measuring efanesoctocog alfa FVIII activity in one‐stage clotting assays (OSAs) and chromogenic substrate assays (CSAs).
Methods
Human plasma with no detectable FVIII activity was spiked with efanesoctocog alfa or a full‐length recombinant FVIII product comparator, octocog alfa, at nominal concentrations of 0.80 IU/mL, 0.20 IU/mL, or 0.05 IU/mL, based on labelled potency. Clinical haemostasis laboratories (N = 35) tested blinded samples using in‐house assays. Data from 51 OSAs (14 activated partial thromboplastin time aPTT reagents) and 42 CSAs (eight kits) were analyzed.
Results
Efanesoctocog alfa activity was reliably (±25% of nominal activity) measured across all concentrations using OSAs with Actin FSL and multiple other aPTT reagents. Under‐ and overestimation of FVIII activity occurred with some reagents. No specific trend was observed for any class of aPTT activators. A two‐ to three‐fold overestimation was consistently observed using CSAs and the OSA with Actin FS as the aPTT reagent across evaluated concentrations.
Conclusion
Under‐ or overestimation occurred with some specific OSAs and most CSAs, which has been previously observed with other modified FVIII replacement products. Efanesoctocog alfa FVIII activity was measured with acceptable accuracy and reliability using several OSA methods and commercial plasma standards.
Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a ...new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa–tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood–based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency.
We describe two children with significant bleeding: one with multiple ecchymoses and the other with scrotal bleeding. In both patients, the activated partial thromboplastin time (APTT) was prolonged, ...with positivity for lupus anticoagulants (LA). However, the Owren prothrombin time (PT), usually insensitive for LA, was also prolonged. The presence of LA is associated with diverse clinical manifestations, with most patients being asymptomatic while others present venous or arterial thrombosis. Bleeding in conjunction with LA is rare and it is unusual to see prolongation of the Owren PT assay due to LA. An extended laboratory investigation of one of the patient’s plasma revealed not only LA but also a specific nonphospholipid-dependent antiprothrombin antibody causing an acquired hypoprothrombinemia.
Conclusion:
It is likely that the low prothrombin activity and not the LA caused the bleeding. The bleeding signs and symptoms in both patients subsided when the PT was normalized, although the prolonged APTT and the LA remained.
The mutation G17736A/Val107Val (silent) was found in five of a total of 86 families with haemophilia B in Sweden. It is unlikely that five families with analogous clinical expression will have the ...same polymorphism, which is not found in other patients or normal subjects, or that they will be the only families in the population without any other causative mutation. All affected individuals in the five families were found to have factor IX (F9) coagulation activity 15–20 U dL−1, corresponding F9 protein levels and the same clinical history of mild haemophilia. Lymphocyte mRNA was extracted from one of the haemophiliacs and from a healthy male. RT‐PCR of the mRNA and subsequent PCR amplification produced cDNA fragments of the same length from the patient and the normal subject, indicating no exon skipping or retention of introns. Sequencing of cDNA from codon 68 in exon D to codon 180 in exon F revealed that the patient had the G17736A mutation but no other abnormalities. We conclude that G17736A/Val107Val causes mild haemophilia B. Although, exon skipping and retention of introns can be excluded as pathophysiological mechanisms, it is plausible that the studied mutation has more subtle effects on a splicing site or interferes with a splicing enhancer site. Also, changes to synonymous codons may reduce the translation rate and thereby alter F9 protein folding in vivo, which would explain the phenotype. Confirmation of these assumptions requires methods that are more sensitive than those available today, and our discussion illustrates the existing obstacles.
Replacement therapy with factor IX (FIX) concentrates is the recommended treatment for patients with hemophilia B, an X-linked bleeding disorder occurring in 1:25 000 male births. N9-GP is a ...recombinant FIX molecule with a prolonged half-life which is obtained by site-directed glycoPEGylation where a 40-kDa polyethylene glycol molecule is attached to the activation peptide of FIX. This first human dose trial in patients with hemophilia B investigated the safety and pharmacokinetic properties of a single IV dose of N9-GP. Sixteen previously treated patients received one dose of their previous FIX product followed by one dose of N9-GP at the same dose level (25, 50, or 100 U/kg). None of the patients developed inhibitors. One patient developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from pharmacokinetic analyses. In the remaining 15 patients, N9-GP was well-tolerated. The half-life was 93 hours, which was 5 times higher than the patient's previous product. The incremental recovery of N9-GP was 94% and 20% higher compared with recombinant and plasma-derived products, respectively. These results indicate that N9-GP has the potential to reduce dosing frequency while providing effective treatment of bleeding episodes with a single dose. The trial was registered at www.clinicaltrials.gov as NCT00956345.
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.
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.
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.
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.).
Female haemophilia A caused by skewed X inactivation KNOBE, K. E.; SJÖRIN, E.; SOLLER, M. J. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
July 2008, Letnik:
14, Številka:
4
Journal Article
Introduction
The use of factor VIII (FVIII) replacement products enables comprehensive management (prophylaxis, acute bleed control, and perioperative hemostasis) of patients with severe hemophilia ...A. Prophylaxis with standard half-life FVIII replacement therapies requires frequent administration, and low FVIII activity levels between infusions lead to an increased risk of bleeds. FVIII replacement products that achieve optimal bleed protection with once-weekly dosing intervals remain an unmet need for people living with severe hemophilia A.
BIVV001 (rFVIIIFc-VWF-XTEN) is a novel FVIII therapy composed of single-chain FVIII, the Fc domain of human immunoglobulin G1, the FVIII-binding D′D3 domain of von Willebrand factor (VWF), and 2 XTEN polypeptides. BIVV001 is designed to be a next-generation FVIII therapy that circulates independently of endogenous VWF, thereby breaking the VWF-imposed half-life ceiling.
Single-dose BIVV001 was well tolerated and provided sustained FVIII activity in a first-in-human trial (Konkle et al, Blood, 2018). Here, we report final data for an open-label Phase 1 trial to assess the safety, tolerability, and pharmacokinetics (PK) of repeat dosing with BIVV001 in subjects with severe hemophilia A (<1 IU/dL <1% endogenous FVIII) (EudraCT No: 2018-001535-51).
Methods
Eligible subjects were 18-65 years of age, had severe hemophilia A, and ≥150 exposure days to prior FVIII products. After screening and washout, subjects received 4 once-weekly doses of BIVV001 (Days 1, 8, 15, and 22) at either 50 IU/kg (Cohort 1) or 65 IU/kg (Cohort 2). The safety observation period extended for 28 days after the last dose of BIVV001. Primary endpoints were the occurrence of adverse events and clinically significant abnormalities in laboratory tests, including inhibitor development. Secondary endpoints were PK parameters derived from FVIII activity evaluated using a one-stage activated partial thromboplastin time clotting assay. PK blood samples were collected immediately before BIVV001 infusion on Days 1, 8, 15, and 22 and at multiple times after dosing on Days 1 and 22.
Results
All subjects enrolled in Cohort 1 (n=10) and Cohort 2 (n=14) completed the study. Mean (range) age of subjects was 35 (25-55) years for Cohort 1 and 41 (24-58) years for Cohort 2. BIVV001 was well tolerated. No inhibitor development to FVIII was detected, and there were no events of hypersensitivity or anaphylaxis reported.
Baseline-corrected PK data were available for 9 subjects in Cohort 1 and all subjects in Cohort 2. Consistent with the single-dose study, the geometric mean (range) half-life for 50 IU/kg and 65 IU/kg BIVV001 was 41.3 (34.2-50.1) hours and 37.3 (28.9-43.8) hours, respectively. After 4 weekly doses of BIVV001 (Day 22), geometric mean (range) area under the activity-time curve from hour 0 over the dosing interval (AUC0-tau) and maximum concentration at steady state (Cmaxss) of BIVV001 were 8290 (5810-10,300) hr × IU/dL and 131 (96-191) IU/dL for Cohort 1 and 11,200 (7040-15,800) hr × IU/dL and 171 (118-211) IU/dL for Cohort 2, respectively. Mean (standard deviation) FVIII activity immediately prior to the final dose of BIVV001 (Ctrough) was 9.9 (2.8) IU/dL in Cohort 1 and 11.7 (5.5) IU/dL in Cohort 2. The mean (range) Day 22-Day 1 accumulation index was 1.07 (1.03-1.11) for Cohort 1 and 1.05 (1.02-1.08) for Cohort 2. At 5 and 7 days after the final BIVV001 infusion, mean steady-state FVIII activity was 22% and 10% for Cohort 1 and 27% and 12% for Cohort 2, respectively (Figure). Geometric mean (range) incremental recovery after the first dose of BIVV001 was 2.3 (1.6-2.8) IU/dL per IU/kg for Cohort 1 and 2.4 (1.6-3.3) IU/dL per IU/kg for Cohort 2.
Conclusions
Four weekly infusions of 50 IU/kg or 65 IU/kg BIVV001 were well tolerated with no identified safety concerns. FVIII activity levels were sustained and nonaccumulating between doses. By breaking through the VWF-imposed half-life ceiling, BIVV001 prophylaxis may lead to more optimal, extended protection against bleeds for patients with severe hemophilia A than standard FVIII therapies. These results support the continued development of BIVV001 in a Phase 3 clinical trial program.
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Lissitchkov:Roche: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Sanofi: Equity Ownership, Research Funding; Bayer: Consultancy, Equity Ownership, Honoraria, Other: Principal investigator for clinical trials, Research Funding; Sobi: Consultancy, Equity Ownership, Honoraria; Shire: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Octapharma: Equity Ownership, Research Funding. Rice:Sanofi: Employment. Katragadda:Sanofi: Employment. Willemze:Sanofi: Employment. Benson:Sanofi: Employment. Knobe:Sanofi: Employment.
Background: nonacog beta pegol (N9‐GP) is a glycoPEGylated recombinant factor IX (rFIX) molecule with a prolonged half‐life. Objectives: To provide information on potential dose regimens for N9‐GP ...for phase 3 pivotal and surgery trials. Methods: A population pharmacokinetic model was developed from single‐dose data derived from the first human‐dose trial with N9‐GP in hemophilia B patients, and was used to extrapolate to steady‐state conditions for different N9‐GP dose regimens for prophylaxis. The model was also used to compare prophylaxis using N9‐GP with standard prophylactic regimens using rFIX or plasma‐derived (pd) FIX (40 IU kg−1 every third day). Plasma activity following dosing with N9‐GP, rFIX and pdFIX for surgery and on‐demand treatment of bleeds was also simulated. Results: A linear two‐compartmental model best described the pharmacokinetic profiles of N9‐GP, rFIX and pdFIX. A prophylactic regimen of 10 U kg−1 N9‐GP once weekly predicted mean peak and trough levels of 18 and 4.2 U dL−1, while 40 U kg−1 once weekly predicted values of 72 and 17 U dL−1, respectively. Standard prophylactic regimens with rFIX and pdFIX predicted mean peak and trough levels of 34 and 3.9 IU dL−1 for rFIX, and mean values of 43 and 2.1 IU dL−1 for pdFIX. Additional simulations predicted significantly reduced dosing frequency and factor concentrate consumption for N9‐GP vs. rFIX and pdFIX for surgery and the treatment of bleeds. Conclusions: N9‐GP may allow prophylaxis, surgical dosing regimens and on‐demand treatment of bleeding episodes with less frequent injections and lower factor concentrate consumption; this possibility is being investigated in prospective clinical trials.
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