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Subcutaneous Marzeptacog Alfa (Activated) for On‐Demand Treatment of Bleeding Events in Subjects With Hemophilia A or B With Inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacokinetics and Quantitative Pharmacology)ORCID iD: 0009-0009-0165-363X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Department of Pharmacy Uppsala University Uppsala Sweden. (Pharmacometrics Group)ORCID iD: 0000-0002-2839-4940
Catalyst Biosciences South San Francisco California USA.
Catalyst Biosciences South San Francisco California USA.
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2024 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 115, no 3, p. 498-505Article in journal (Refereed) Published
Abstract [en]

Marzeptacog alfa (MarzAA) is under development for subcutaneous treatment of episodic bleeds in patients with hemophilia A/B and was studied in a phase III trial evaluating MarzAA compared with standard-of-care (SoC) for on-demand use. The work presented here aimed to evaluate MarzAA and SoC treatment of bleeding events on a standardized four-point efficacy scale (poor, fair, good, and excellent). Two continuous-time Markov modeling approaches were explored; a four-state model analyzing all four categories of bleeding improvement and a two-state model analyzing a binarized outcome (treatment failure (poor/fair), and treatment success (good/excellent)). Different covariates impacting improvement of bleeding episodes as well as a putative relationship between MarzAA exposure and improvement of bleeding episodes were evaluated. In the final four-state model, higher baseline diastolic blood pressure and higher age (> 33 years of age) were found to negatively and positively impact improvement of bleeding condition, respectively. Bleeding events occurring in knees and ankles were found to improve faster than bleeding events at other locations. The covariate effects had most impact on early treatment success (≤ 3 hours) whereas at later timepoints (> 12 hours), treatment success was similar for all patients indicating that these covariates might be clinically relevant for early treatment response. A statistically significant relationship between MarzAA zero-order absorption and improvement of bleedings (P < 0.05) were identified albeit with low precision. No statistically significant difference in treatment response between MarzAA and intravenous SoC was identified, indicating the potential of MarzAA for treatment of episodic bleeding events with a favorable subcutaneous administration route.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024. Vol. 115, no 3, p. 498-505
National Category
Hematology
Identifiers
URN: urn:nbn:se:uu:diva-521050DOI: 10.1002/cpt.3172ISI: 001143479000001OAI: oai:DiVA.org:uu-521050DiVA, id: diva2:1829094
Available from: 2024-01-17 Created: 2024-01-17 Last updated: 2024-04-03Bibliographically approved
In thesis
1. Pharmacometric models to inform dose selection and study design: Applied in hemophilia and tuberculosis
Open this publication in new window or tab >>Pharmacometric models to inform dose selection and study design: Applied in hemophilia and tuberculosis
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

While tuberculosis is a global pandemic, hemophilia is a rare disease which many have not heard of. Due to tuberculosis mainly being a problem in developing countries and hemophilia being a rare disease, they are not as heard of as other diseases such as cancer or metabolic diseases which are on the rise in Western societies. The quality of life for patients suffering from these diseases is notably impaired and novel drugs are warranted to further improve the treatment and management of both diseases. As market incentives are a limiting factor, it is important that the efforts that are taken to develop novel drugs are carried out in an informative manner.   One strategy to incorporate as much information as possible to inform decision making in drug development is to use pharmacometric methods. Such strategies enable simultaneous analysis of different types of data that are generated during drug development programs. In this thesis, the aim was to develop and apply pharmacometric models to facilitate dose selection and study designs in clinical programs that aim at developing new drugs for tuberculosis and hemophilia.   A standardized analysis approach of early clinical trials studying drugs against tuberculosis was presented including power calculations that showed the number of patients needed to detect drug effects. Such efforts are important as showing drug effect in early trials will aid decision making into significantly longer and costlier late trials. The approach was used to analyze a clinical trial studying if the current dose of meropenem can be lowered without negatively impacting drug effects and improving the already poor tolerability of the drug. The study found that lowering the dose may lower activity without any improvement of the tolerability properties. Furthermore, population pharmacokinetic models were developed for two novel hemostatic drugs in development for prophylactic and on-demand treatment of hemophilia. Based on the models, clinical trials in adult and pediatric subjects were supported. One of the trials were performed and it was showed with a model-based analysis that the new drug which is given subcutanously has similar efficacy as current intravenously given standard of care alternatives. Using the developed models, different strategies for designing pharmacokinetic trials in children was also presented.   In conclusion, the work performed within this thesis has contributed to the development of new drugs against tuberculosis and hemophilia.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2024. p. 86
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 346
Keywords
drug development, pharmacometrics, pharmacokinetics, pharmacodynamics, non-linear mixed effect models, hemophilia, tuberculosis, dose selection, study design, pediatric extrapolation
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-521052 (URN)978-91-513-2017-5 (ISBN)
Public defence
2024-03-08, room A1:107a, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2024-02-15 Created: 2024-01-18 Last updated: 2024-02-15

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