Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study

Oldenburg, Johannes; Shima, Midori; Kruse‐Jarres, Rebecca; Santagostino, Elena; Mahlangu, Johnny; Lehle, Michaela; Bienz, Nives Selak; Chebon, Sammy; Asikanius, Elina; Trask, Peter C.; Mancuso, Maria Elisa; Jiménez‐Yuste, Víctor; Mackensen, Sylvia von; Lévy, Gallia

doi:10.1002/pbc.28474

Cited by 15 publications

(32 citation statements)

References 35 publications

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“…The population exposure-efficacy analysis described here used data from one Japanese phase I/II study [22,23] and four phase III studies: HAVEN 1 [25], HAVEN 2 [26], HAVEN 3 [27], and HAVEN 4 [28], as well as a non-intervention study [30][31][32]. The designs, baseline characteristics, and clinical findings of those studies are summarized in Table 1.…”

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

“…The designs, baseline characteristics, and clinical findings of those studies are summarized in Table 1. The data set included data from a total of 445 PwHA; 60 of them only participated in the non-intervention studies [30][31][32], thus data from 385 emicizumab-treated PwHA were included. Study arms where emicizumab was not given were included in the analysis to provide more information on the distribution of bleeds in the absence of emicizumab.…”

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

“…Study arms where emicizumab was not given were included in the analysis to provide more information on the distribution of bleeds in the absence of emicizumab. Among PwHA treated with emicizumab, 64 had previously participated in the non-intervention study [30][31][32] and later enrolled in the interventional trials. In addition, in studies HAVEN 1 and HAVEN 3 [25,27], 6-month data from the study period pre-emicizumab introduction were collected.…”

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

“…The non-intervention study [30][31][32] and HAVEN 2 [26] were single-arm studies. Persons with hemophilia A with Emicizumab is a recombinant, humanized, bispecific monoclonal antibody that simultaneously binds to FIXa and FX, thereby mimicking the cofactor function of activated FVIII [16][17][18].…”

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

“…In addition, 64 PwHA participated that went on to later participate in HAVEN 1 [25] e Two PwHA were excluded from model development because of very low albumin values at baseline [31] f Four PwHA in this study were not included in the PK model development [31] as no emicizumab doses were administrated or no PK information was collected. However, data from the nonintervention period in these four PwHA were included Study Japanese phase I/II study [22,23] HAVEN 1 [25] Non-intervention study [30][31][32] HAVEN 2 [26] HAVEN 3 [27] HAVEN 4 [ factor VIII inhibitors were enrolled in HAVEN 2. At the cut-off date used for the present analysis, all PwHA in the pediatric HAVEN 2 were given a maintenance dose of 1.5 mg/kg QW SC.…”

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

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Exposure–Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII

et al. 2021

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Background and Objective Emicizumab is a monoclonal antibody that bridges activated coagulation factor IX and factor X to restore effective hemostasis in persons with hemophilia A. It is indicated for routine prophylaxis of bleeding episodes in persons with hemophilia A. The aim of the present study is to describe the exposure-response relationship between emicizumab concentrations and bleeding frequency, and to confirm adequate bleeding control of the investigated dosing regimens 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks. Methods Treated bleeding events were pooled from 445 persons with hemophilia A with and without inhibitors against factor VIII, participating in six clinical studies. Emicizumab concentrations were predicted using a previously developed population pharmacokinetic model. A count model was used to quantify the exposure-response relationship. These models were used to illustrate the relationship between emicizumab concentrations and cumulative count of bleeding over 1 year (annualized bleeding rate). Results The final exposure-response model, based on a generalized Poisson distribution and an inhibitory E max relationship, adequately describes the relationship between daily emicizumab concentrations and daily bleed frequency. A significant effect of factor VIII prophylaxis among persons with hemophilia A without inhibitors was found. Annualized bleeding rate simulations show that the three emicizumab dosing regimens maintain the concentrations close to the plateau of the effect. At the average steady-state concentration across all regimens (53.5 µg/mL), the predicted mean annualized bleeding rate is 1.28, corresponding to a 94.0% reduction from baseline. Conclusions These results confirm that average emicizumab concentrations achieved with all three emicizumab dosing regimens provide adequate bleeding control.

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Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

Section: Clinical Studies Subjects and Datamentioning

confidence: 99%

See 3 more Smart Citations

Exposure–Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII

et al. 2021

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Pediatric Rare Diseases Development in the Pharmaceutical Industry: An International Consortium for Innovation and Quality in Pharmaceutical Development, Clinical Pharmacology Leadership Group‐Pediatrics Working Group, Rare Diseases Subteam Whitepaper Examining the Current Landscape and Recommendations for the Future

Krishna,

Sebastien,

Corriol‐Rohou

et al. 2024

Clin Pharma and Therapeutics

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Many new opportunities surround rare pediatric disease drug development, thanks to key advances in regulatory thinking and in the scientific community. As rare disease drug development brings challenges to the developers in terms of limited understanding of natural history, heterogeneity in drug response, as well as difficulty recruiting patients in pivotal trials, there has never been a greater need for quantitative integration. To understand how International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) member companies approach pediatric rare disease drug development, the rare pediatric subteam of the Clinical Pharmacology Leadership Group (CPLG) sponsored Pediatrics Working Group conducted a baseline survey to assess the four main pillars of this quantitative innovation, namely, biomarkers and surrogate end points, statistical methodologies, model‐informed drug development, as well as public–private partnerships. The survey was administered by IQ and yielded 13 evaluable responders from represented companies. This article presents the key findings from this baseline identifying survey, highlighting the key blind spots, and providing insightful expert opinions to address those gaps. In summary, we call an urgent attention to the community on the opportunities to enhance integration and within‐industry learnings from this analysis on aspects related to platform studies, end‐to‐end quantitative integration, and sharing of trial‐level placebo data for better understanding of disease progression and more efficient trial designs. We collectively hope that these findings will stimulate discussion and debate around cross‐industry sharing and collaboration to better delineate principles and further enhance the efficiency of rare pediatric disease drug development.

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Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3

Callaghan

Asikanius

Lehle

et al. 2022

Research and Practice in Thrombosis and Haemostasis

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Background Bleeding in people with hemophilia A can be life threatening, and intra‐articular bleeds can result in joint damage. Most clinical studies focus on treated bleeds, while bleeds not treated with coagulation factor(s) (untreated bleeds) are underreported. Objectives We assessed the incidence of untreated bleeds during a noninterventional study (NIS) wherein people with hemophilia A, with or without factor VIII (FVIII) inhibitors, were managed according to standard practice. Patients/Methods Using the Bleed and Medication Questionnaire, we prospectively collected data from three cohorts: Cohort A, adults/adolescents (age ≥12 years) with FVIII inhibitors; Cohort B, children (aged <12 years) with FVIII inhibitors; Cohort C, adults/adolescents without FVIII inhibitors. Untreated bleeds were analyzed for site, frequency, and etiology of bleeding and compared with those during emicizumab prophylaxis in the same individuals after transferring to a Phase III HAVEN trial. Results In the 221 participants enrolled in the NIS (Cohort A, n = 103; Cohort B, n = 24; Cohort C, n = 94), the incidence of untreated bleeds was approximately 40% of all bleeds in people with FVIII inhibitors and 26.2% in adolescents/adults without inhibitors. Approximately 70% of treated bleeds and approximately 54% of untreated bleeds in adults/adolescents were in joints. Untreated joint bleeds were less common (7.1%) in children. Overall, intra‐individual comparisons showed reduced treated/untreated bleeds following transition from standard to emicizumab prophylaxis. Conclusion A significant proportion of bleeding events are untreated in people with hemophilia A. There is a need to further understand why bleeds remain untreated and to capture such events in clinical studies.

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Outcomes in children with hemophilia A with inhibitors: Results from a noninterventional study

Cited by 15 publications

References 35 publications

Exposure–Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII

Exposure–Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII

Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3

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