Objective:
The completed pediatric phase 3 pathfinder 5 trial assessed the safety and efficacy of N8-GP (turoctocog alfa pegol, ESPEROCT®) use for routine prophylaxis and treatment of breakthrough bleeds in previously treated children.
Methods:
pathfinder 5 was a multicenter, multinational, single-arm study evaluating safety, efficacy, and pharmacokinetics. Children (aged <12) with severe hemophilia A were administered prophylaxis (target 60 [50-75] IU/kg twice weekly) in the main phase (26 weeks) followed by an extension phase. Current analysis covers study initiation (February 2013) through completion (September 2018).
Summary:
Of the 68 children (34 aged 0-5, 34 aged 6-11) enrolled, 63 completed the main phase and 62 completed the extension. Most (95%) were previously on prophylaxis. The total study period amounted to 306 patient-years (32,138 exposure days); median (mean) patient exposure was 4.9 (4.5) years.
Overall, 838 adverse events (AEs) were reported; 18 serious AEs included 2 possibly/probably related to N8-GP (severe allergic reaction [1] and increasing bleeding symptoms [1]). No inhibitor development was observed in the trial. Two AEs resulted in withdrawal; a third patient with severe allergic reactions (after 4 doses) that resolved after 2 hours without any treatment met preestablished withdrawal criteria. There were no anti-PEG antibodies of clinical significance; however, 21 (31%) patients had anti-PEG antibodies at baseline (prior to exposure), and 1 patient had a single positive measurement after exposure at a titer <1.
Overall, 55 patients (81%) reported 330 bleeds during the study; most were traumatic (67%). The success rate for hemostasis was 84% (excellent/good); 71% were treated with 1 injection, and 88% of patients were successfully treated with 1-2 injections. Median (mean) utilization for bleeds was 68 (95) IU/kg.
Median ABRs are shown below; estimated mean ABR was 1.1. Forty-seven percent of children had no spontaneous bleeds throughout the trial. Of 13 children with 17 target joints at baseline, 77% (main phase) and 46% (complete trial) reported no bleeds in their target joints. For those previously on prophylaxis, the mean observed ABR was 2.3 compared with the historical ABR of 6.4. The mean prophylaxis dose was 64.7 IU/kg with an interval of 3.5 days.
| Median ABR | Age 0-5 y | Age 6-11 y | Total |
| Overall | 0.6 | 0.9 | 0.8 |
| Spontaneous | 0.1 | 0.2 | 0.2 |
| Traumatic | 0.3 | 0.8 | 0.5 |
N8-GP prolonged single dose half-life by 1.9x compared with the child’s prior FVIII product. The mean trough levels on twice-weekly dosing were 0.019 IU/mL (0.016 ages 0-5, 0.024 ages 6-11).
Conclusion:
These data support the safety and efficacy of N8-GP in a controlled phase 3 trial setting in children. Prophylaxis with N8-GP using a consistent dose/interval (65 IU/kg twice weekly) was effective in preventing bleeds. No unexpected safety issues were identified.
Objective:
The adolescent/adult pivotal phase 3 pathfinder 2 trial assessed N8-GP (turoctocog alfa pegol, ESPEROCT®) use for routine prophylaxis and treatment of bleeds in previously treated patients (PTPs).
Methods:
pathfinder 2 was a multi-center, multi-national, single-arm study evaluating safety, efficacy and pharmacokinetics. Adolescents/adults (aged ≥12 y) with severe hemophilia A were administered prophylaxis (50 IU/kg Q4D) in the main phase with option for eligible patients (0-2 bleeds in prior 6 months) to randomize (2:1) to 75 IU/kg Q7D or 50 IU/kg Q4D during extension 1 (24 weeks) and continue treatment into extension 2. An on-demand group was included throughout. Current analysis covers January 2012 through December 2018.
Summary:
Of the 186 PTPs (including 46 [25%] from the US) enrolled in the main phase, 150 (81%) started extension 1, 139 (75%) completed extension 1, and 128 (69%) completed the study. Mean age was 31.1 years, weight 75 kg and BMI 24.3.
The complete trial covers 785 patient-years of treatment (66,577 exposure days [ED]) during which there were 2,758 bleeds, including 1,807 (66%) spontaneous bleeds and 1,735 (63%) joint bleeds. Twelve patients treated on-demand for a mean 3.1 years reported nearly half of all bleeds (1,270, 46%), including 971 (54%) spontaneous bleeds and 627 (36%) joint bleeds. Hemostatic efficacy was rated excellent/good in 2,470 (90%) episodes; 2,614 bleeds (95%) were treated with 1-2 injections.
Of 175 patients on prophylaxis, 55 of 110 eligible were randomized in extension 1. For 177 patients treated with 50 IU/kg Q4D prophylaxis for 613 years (57,723 ED), 126 (71%) experienced 1,312 bleeds. For 61 low-bleed patients with 134 years (7,255 ED) on 75 IU/kg Q7D prophylaxis, 53 (87%) experienced 176 bleeds. Median ABRs are shown in the TABLE.
| 50 IU/kg Q4D | 75 IU/kg Q7D | |
| n | 177 | 61 |
| Mean treatment | 3.5 years | 2.2 years |
| Median ABR | 0.8 | 1.7 |
N8-GP mean trough levels were 3.1 IU/dL on 50 IU/kg Q4D and 1.0 IU/dL on 75 IU/kg Q7D.
A total of 1,827 adverse events were reported over 785 exposure years, including 63 serious adverse events. One patient with an intron 22 inversion developed a low-titer inhibitor at 93 ED and was withdrawn when it progressed to >5 BU. Non-neutralizing anti-PEG antibodies were seen at baseline in 12 patients (6.5%) prior to first N8-GP exposure and 11 (5.9%), who had negative anti-PEG at baseline, had positive antibodies after exposure.
Conclusion:
These data support the safety and efficacy of N8-GP in a controlled phase 3 trial setting in adolescents/adults. Prophylaxis with N8-GP with a consistent dose/interval (50 IU/kg Q4D) was effective in preventing bleeds; extended dosing was evaluated as successful for a subgroup of low-bleed patients. No significant safety issues were identified.
Background:
US Hemophilia Treatment Center (HTC) care reduces mortality and hospitalizations, and guidelines recommend this care model. Yet national data that uniformly and longitudinally monitors patient experience with HTC care is limited.
Objective:
To assess patient satisfaction with HTC services and clinicians over time.
Methods:
The US HTC Network conducted the first ever nationally uniform patient satisfaction surveys on care received in 2014 and 2017. A Regional workgroup devised, piloted, and finalized an electronic, two-page survey for self-administration at clinic, or at home, in English or Spanish. Content was based on national instruments to enhance comparability and scientific robustness. Questions assessed demographics; satisfaction with HTC team members and services; insurance and language barriers. Respondents were anonymous but identified their HTC. Participation was voluntary. Patients with HTC contact in 2014 and 2017 were eligible. Data were collected for 4 months in 2015 and 6 in 2018; on average 130 HTCs (94%) from all US regions participated. Parents completed surveys for children under age 18. Data were entered, analyzed and aggregated at national, regional and HTC levels at a central site.
Results:
5006 and 4767 persons participated, respectively, in 2015 and 2018. In both years, over 1400 (30%) respondents were female, nearly 80% were White, and 10% Hispanic. On average, 3038 had Factor 8 or 9, 1280 Von Willebrand, 186 other factor deficiencies and 369 other bleeding disorders. Respondents reported being ‘always’ or ‘usually’ (A/U) satisfied with HTC staff and services from 90% - 97% of the time in both 2014 and 2017. In both years, >4400 gave these highest A/U ratings for HTC Hematologists and Nurses; 3300 for Social Workers; >2600 for Physical Therapists; 1400 for Genetic Counselors, and >1100 for Psychologists. In both years, 96% were A/U satisfied overall with HTC services. Over 95% gave the A/U satisfaction ratings both years for these services: getting needed care and information, being treated respectfully, spending sufficient time with staff, and involved in shared decision making. 82% and 91% of respondents, respectively, gave the A/U satisfaction ratings for care coordination with primary care providers and other specialists. Over 90% of >700 youth age 12-17 gave HTC teen transition services the A/U satisfaction ratings both years. 96% of >2760 respondents reported A/U satisfaction with their HTC Pharmacy (340B) Factor Program in 2017. Insurance and language barriers to HTC care posed problems A/U for 27% and 15%, respectively both years.
Conclusions:
Patients consistently report high levels of satisfaction with HTCs, documenting HTC value over time. Patient satisfaction influences treatment adherence, can influence reimbursement, and is increasingly required by payers. A national uniform survey is feasible to conduct using a regional structure to implement, is well received by patients, and provides critical information to stakeholders.
Dr. Meeks is an Associate Professor of Pediatrics in the Department of Pediatrics at the Emory University School of Medicine and the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. She obtained a Bachelor of Science in Mathematics from Duke University where she was elected to Phi Beta Kappa. After earning her medical degree from the University of Mississippi, she completed her clinical training at the University of Virginia and Emory University. Dr. Meeks has a basic, translational, and clinical research interest in the development of inhibitors in hemophilia A. Her work has focused on the early immune response to factor VIII and the diversity of the B-cell response to factor VIII. She is a former NHF clinical fellow who currently has funding to pursue these projects from the Hemostasis and Thrombosis Research Society and the National Institutes of Health.
