To assess the safety and effectiveness of turoctocog alfa in previously treated patients (PTPs) and previously untreated patients (PUPs) with haemophilia A in a real-world setting in Japan.
This ...multicentre, non-interventional, post-marketing study recruited patients with haemophilia A who initiated treatment with turoctocog alfa from 18 sites (08/2014-12/2018). The primary endpoint was adverse events (AEs) during the 2-year study period.
The safety and effectiveness analysis set included 39 patients. In total, 13 (33.3%) patients reported ≥1 AE; incidence rate was 60.4 events/100 patient-years of exposure (PYE). Treatment was withdrawn in two cases: pruritus in a PTP and factor VIII inhibitor development in a PUP. Inhibitor development occurred in 2.6% of all patients, with an incidence rate of 3.8 events/100 PYE. The rate of inhibitor development was 0%, 25% and 20% in PTPs, PUPs and PUPs with severe type, respectively. The haemostatic success rate was 91.4% for 383 bleeding episodes and 85.7% for 14 surgeries. The negative binomial annualised bleeding rate for the prophylaxis regimen was 6.19 episodes/year (95% CI, 3.69-10.38). The mean (SD) total consumption of turoctocog alfa (
= 34; excluding FVIII inhibitors) was 5,382.6 (7,180.1) IU/kg/year/patient; consumption was 4,133.1 (1,452.4) IU/kg/year/patient for prophylaxis.
The effectiveness and safety profiles were comparable to those observed in other turoctocog alfa trials; effectiveness analysis and consumption were not affected by treatment regimens.
Long-term use of turoctocog alfa therapy in clinical practice posed no newly identified safety issues and was effective for prophylaxis and treatment of bleeds in patients with haemophilia A in Japan.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Currently, the mainstay of disease management for hemophilia B, a hemorrhagic disease caused by a congenital deficiency or molecular abnormalities of blood coagulation factor IX (FIX), is prophylaxis ...using FIX concentrate. On-demand injections of FIX concentrate may also be required, even during prophylaxis, when a patient with hemophilia B is bleeding. Albutrepenonacog alfa (rFIX-FP) is a human albumin fusion gene recombinant FIX, which is administered once every seven, 14, or 21 days, depending on patient preferences and symptoms. Studies have demonstrated its efficacy and safety in a range of patients; however, to date, reports of real-world experiences of the use of rFIX-FP in Japan are limited. We present a case series of three Japanese individuals with moderately severe (FIX activity 1 to <2%) or severe (FIX activity <1%) hemophilia B who benefited from prophylaxis using rFIX-FP in our clinical practice setting. We highlighted the good effectiveness of rFIX-FP in a patient with moderately severe hemophilia B who required prophylaxis due to joint bleeding, which was causing deterioration of his left ankle joint, as well as in a patient with severe hemophilia B and atherothrombotic cerebral infarction, whose trough level had to be ≥5% for concomitant use of an antiplatelet drug, and in a patient with severe hemophilia B who was working in nursing care, which involved heavy labor and night shifts, and who had previously been treated with on-demand FIX concentrate. In all three cases, rFIX-FP improved disease symptoms, and the patients were able to maintain steady states of therapy due to the treatment characteristics of rFIX-FP, which stabilizes FIX at high trough levels.
IntroductionFor persons with haemophilia A with factor (F) VIII inhibitors (PwHAwI), immune tolerance induction (ITI) therapy is indicated for inhibitor eradication; however, since PwHAwI on ITI were ...excluded from the emicizumab clinical development programme, there are limited safety data for emicizumab treatment under/immediately after ITI in PwHAwI. Accordingly, there is a need to collect safety and efficacy data on this concomitant treatment strategy. The AKATSUKI study aims to evaluate the safety of emicizumab under/immediately after ITI in PwHAwI; here we report details of the study protocol.Methods and analysisAKATSUKI is an open-label, non-randomised, interventional, multicentre study. Twenty participants with congenital HA with FVIII inhibitors will be enrolled from 17 sites across Japan. Emicizumab will be administered subcutaneously, with an initial loading dose of 3 mg/kg once per week (QW) for the first 4 weeks, followed by a maintenance dose of 1.5 mg/kg QW, 3 mg/kg once every 2 weeks or 6 mg/kg once every 4 weeks. For ITI therapy, 50 IU/kg FVIII will be administered three times per week. For extended half-life FVIII, a dosing frequency of twice per week will be permitted. The primary endpoint is a comprehensive safety evaluation of adverse events (mainly thromboembolic events) and abnormal laboratory values over time. Secondary endpoints are the number of bleeds requiring coagulation factor treatment, the number of participants achieving a partially successful ITI response, FVIII inhibitor titres under/immediately after ITI, quality of life and time to achieve a negative FVIII inhibitor result (<0.6 BU/mL) and partial success in PwHAwI starting ITI after study enrolment.ConclusionsAKATSUKI will evaluate the safety of emicizumab administered under/immediately after ITI, providing reference data to inform treatment strategies in PwHAwI.Ethics and disseminationThe results of this study will be published in a peer-reviewed international journal and presented at national and/or international medical scientific conferences; the major findings of this study will be published on the jRCT registry website (https://jrct.niph.go.jp).Trial registration numberjRCTs041200037.
Treatment of congenital hemophilia A (HA) in Japan has greatly improved with the widespread adoption of prophylactic factor (F)VIII concentrates. However, it is unknown ifhas translated into a ...real‐world reduction in disease and treatment burden.
To describe HA disease burden in Japan based on information from two medical information databases, JMDC and Real World Data Co., Ltd. (RWD).
Eligible individuals were diagnosed with congenital HA and prescribed FVIII concentrates, bypassing agents, or emicizumab. Treatment patterns and disease burden data were derived from health insurance claims and electronic medical records.
Data on 459 people with HA were retrospectively collected from 2005 to 2020 in the JMDC database (median min, max of 37 2, 186 months of available records), and 229 people with HA from 1985 to 2020 in the RWD database (median min, max of 154 0, 409 months of available records). Mean (standard deviation) ages at the time of the first record were 25.0 (16.8) years (JMDC) and 19.2 (20.3) years (RWD). In the JMDC database, mean monthly FVIII dose increased from 2201 IU in 2005 to 8239 IU in 2013 to 11,377 IU in 2019; HA‐related drug costs increased accordingly. Mean (95% confidence interval) annual outpatient and out‐of‐hours visits decreased slightly between 2013 and 2019 (outpatient visits: from 22.9 16.8–29.0 to 14.3 12.6–16.1 per person; out‐of‐hours visits: from 1.3 0.2–2.5 to 0.6 0–1.4). There was no change in mean number of hospitalizations.
Challenges remain in HA, including treatment burden, outpatient visits, and hospitalizations.
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Adeno-associated virus (AAV) vectors are promising modalities of gene therapy to address unmet medical needs. However, anti-AAV neutralizing antibodies (NAbs) hamper the vector-mediated therapeutic ...effect. Therefore, NAb prevalence in the target population is vital in designing clinical trials with AAV vectors. Hence, updating the seroprevalence of anti-AAV NAbs, herein we analyzed sera from 100 healthy individuals and 216 hemophiliacs in Japan. In both groups, the overall seroprevalence against various AAV serotypes was 20%–30%, and the ratio of the NAb-positive population increased with age. The seroprevalence did not differ between healthy participants and hemophiliacs and was not biased by the concomitant blood-borne viral infections. The high neutralizing activity, which strongly inhibits the transduction with all serotypes in vitro, was mostly found in people in their 60s or of older age. The multivariate analysis suggested that “60s or older age” was the only independent factor related to the high titer of NAbs. Conversely, a large proportion of younger hemophiliacs was seronegative, rendering them eligible for AAV-mediated gene therapy in Japan. Compared with our previous study, the peak of seroprevalences has shifted to older populations, indicating that natural AAV exposure in the elderly occurred in their youth but not during the last decade.
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The seroprevalence of neutralizing antibody (NAb) against nine AAV serotypes in Japanese hemophilia patients was 20.4%–29.2% and was significantly higher in the 60s or older age than in younger subjects. Many hemophiliacs in Japan, especially in younger age groups, would benefit from AAV-mediated gene therapy.
N8‐GP (turoctocog alfa pegol; Esperoct) is a glycoPEGylated human recombinant factor VIII (FVIII).
Pathfinder8 (NCT01480180) was a phase 3, multinational, open‐label, nonrandomized trial to ...investigate the long‐term safety and efficacy of N8‐GP in people of all ages with severe hemophilia A previously treated with N8‐GP.
Patients were recruited from the completed phase 3 pathfinder2 and pathfinder5 trials to receive intravenous N8‐GP prophylaxis for up to 104 weeks, administered every 7 days, twice weekly, or three times weekly. Primary and secondary end points were the number of adverse events (AEs) reported and efficacy of treatment, respectively.
Overall, 160 patients were exposed to N8‐GP for a mean of 179 exposure days and 681 calendar days (≈1.9 years) per patient. In total, 119 patients experienced 510 AEs, corresponding to a rate of 1.71 AEs per patient‐year of exposure; 97.5% of AEs were mild or moderate in severity, and no AEs led to withdrawal. No patients developed FVIII inhibitors during the trial. The Poisson estimate of mean annualized bleeding rate for all bleeds (excluding surgery) and across all regimens was 1.10 (median, 0.00), and for spontaneous bleeds was 0.61 (median, 0.00). Most (55.6%) patients experienced no bleeds that required FVIII treatment (excluding perioperative bleeds). The estimated hemostatic success rate for the treatment of 322 bleeding episodes (excluding surgery) was 95.8%, including missing values as failure.
Long‐term prophylactic use of N8‐GP appeared safe and efficacious across all age groups in people with severe hemophilia A previously treated with N8‐GP.
