Population pharmacokinetic tools and their uses for determining treatment strategies and therapies for hemophilia A

Abstract

The present disclosure provides, inter alia, methods of treating hemophilia A and computer-based systems, including software-based pharmacokinetic modeling systems, and their use for determining dosing information for subjects with hemophilia A.

Description

[Technical Field]

[0001] Reference to an electronically submitted sequence listing The electronically submitted Sequence Listing XML file (Name: 744011_SA9-488PC_ST26.xml; Size: 33,147 bytes; Created July 25, 2023) is incorporated herein by reference in its entirety.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 370,010, filed August 1, 2022, U.S. Provisional Application No. 63 / 383,091, filed November 10, 2022, and U.S. Provisional Application No. 63 / 485,418, filed February 16, 2023, each of which is incorporated by reference in its entirety for all purposes. [Background technology]

[0003] Although plasma-derived and recombinant clotting factor products enable people with hemophilia to live longer, healthier lives, hemophilia remains one of the most costly and complex conditions to manage. Due to its complexity, treating hemophilia A with FVIII replacement therapy requires a special care management process for physicians, pharmacies, and patients. When assessing a patient's or guardian's ability to provide adequate care, clinicians often evaluate lifestyle habits, psychosocial requirements, and home environment.

[0004] The currently recommended standard of care involves regular administration of FVIII (regular prophylaxis) to minimize the number of bleeding episodes. Regular prophylaxis is associated with improved long-term outcomes but is a demanding regimen limited by the need for frequent intravenous (IV) administration. See Manco-Johnson et al., N Engl J Med. 357(6):535-44 (2007). Extended half-life FVIII products have reduced the frequency of prophylactic FVIII administration, but currently available FVIII products that interact with endogenous von Willebrand factor (VWF) have comparable circulating half-lives, consistent with the upper half-life limit of rFVIII variants due to the half-life of endogenous VWF. See, for example, Pipe et al., Blood. 128(16):2007-16 (2016). Summary of the Invention [Means for solving the problem]

[0005] Provided herein are, inter alia, methods for treating hemophilia A and software-based pharmacokinetic systems and their uses for providing dosing information (such as dose and dosing intervals) for subjects in need of treatment for hemophilia A.

[0006] In some aspects, the disclosure includes methods (e.g., computer-implemented methods) for determining (e.g., calculating, estimating, or providing) efanesectocog alfa dosing information for an individual subject. In some embodiments, the method includes receiving subject-specific information and calculating efanesectocog alfa dosing information using a software-based system, the system being programmed to implement a one-compartment efanesectocog alfa popPK model, the efanesectocog alfa popPK model including body weight as a covariate, and the efanesectocog alfa popPK model not including von Willebrand factor (VWF) level or hematocrit level as a covariate. In some embodiments, the method further includes outputting, by the software-based system, the dosing information for the subject. In some embodiments, the method further includes outputting, by the software-based system, a suggested dosing regimen. In some embodiments, desired treatment outcome information is also received.

[0007] In some aspects, the disclosure includes methods (e.g., computer-implemented methods) of estimating (e.g., calculating, determining, or providing) personalized efanesectocog alfa dosing information for a subject, the method including: (a) receiving, by a processing device, subject information and / or desired treatment outcome information by an application program programmed to operate with an efanesectocog alfa popPK model, wherein the received information is transmitted by one or more electronic devices; (b) calculating, using at least a software-based system, personalized efanesectocog alfa dosing information using the efanesectocog alfa popPK model and the received information; and (c) transmitting the calculated personalized efanesectocog alfa dosing information of (b) to the one or more electronic devices for output of the information, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0008] In some aspects, the disclosure includes methods (e.g., computer-implemented methods) for estimating (e.g., calculating, determining, or providing) personalized efanesectocog alfa dosing information for a subject, the methods comprising: (a) receiving, by one or more electronic devices, subject information and / or desired treatment outcome information; and (b) transmitting, by a processing device, the subject information and / or desired treatment outcome information to an application program, wherein the application is programmed to implement an efanesectocog alfa popPK model. (c) receiving from the application program personalized efanesectocog alfa dosing information calculated using the efanesectocog alfa popPK model and the transmitted information of (b); and (d) outputting by one or more electronic devices the personalized efanesectocog alfa dosing information, wherein the efanesectocog alfa popPK model includes body weight as a covariate and the efanesectocog alfa popPK model does not include VWF level or hematocrit level as a covariate.

[0009] In some aspects, the disclosure includes a method (e.g., a computer-implemented method) for providing (e.g., calculating, determining, or estimating) an efanesectocog alfa dosing regimen based on median popPK, the method including: (a) receiving subject information and / or desired treatment outcome information by a software-based system including an efanesectocog alfa popPK model; (b) calculating, by the software-based system, median PK information using the efanesectocog alfa popPK model and the received information; and (c) outputting, by the software-based system, the median PK information, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0010] In some aspects, the disclosure includes methods (e.g., computer-implemented methods) for providing (e.g., calculating, determining, or estimating) an efanesectocog alfa dosing regimen based on efanesectocog alfa median popPK, the methods including: (a) receiving, by one or more electronic devices, subject information and / or desired treatment outcome information; (b) transmitting, by a processing device, the subject information and / or desired treatment outcome information to an application program, the application being programmed to implement an efanesectocog alfa popPK model; (c) receiving from the application program efanesectocog alfa median PK dosing information calculated using the efanesectocog alfa popPK model and the received information; and (d) outputting, by the one or more electronic devices, the median PK information, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0011] In some aspects, the disclosure includes methods (e.g., computer-implemented methods) of providing (e.g., calculating, determining, or estimating) an efanesectocog alfa dosing regimen, the method including: (a) receiving, by a processing device, subject information and / or desired treatment outcome information by an application program programmed to implement an efanesectocog alfa population pharmacokinetic (popPK) model, wherein the received information is transmitted by one or more electronic devices; (b) calculating, by the application program, personalized efanesectocog alfa dosing information using the efanesectocog alfa popPK model and the received information; and (c) transmitting, by the processing device, the calculated dosing information of the personalized efanesectocog alfa dosing regimen of (b) to one or more electronic devices for output of the information, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0012] In some aspects, the disclosure includes methods (e.g., computer-implemented methods) for estimating (e.g., calculating, determining, or providing) individualized subject phanesoctocog alfa PK information, the methods including: (a) receiving subject information by a software-based system including an phanesoctocog alfa popPK model; (b) estimating, by the software-based system, the individualized subject phanesoctocog alfa PK information using the phanesoctocog alfa popPK model and the received information; and (c) outputting, by the software-based system, the individualized subject phanesoctocog alfa PK information, wherein the phanesoctocog alfa popPK model includes body weight as a covariate and the phanesoctocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0013] In some aspects, the disclosure includes methods (e.g., computer-implemented methods) for estimating (e.g., calculating, determining, or providing) individualized target phanesoctocog alfa PK information, the methods including: (a) receiving, by one or more electronic devices, subject information; (b) transmitting, by a processing device, the subject information to an application program, the application programmed to implement an phanesoctocog alfa popPK model, the application program using the phanesoctocog alfa popPK model and the transmitted information to generate and transmit the individualized subject phanesoctocog alfa PK information; (c) receiving the individualized subject phanesoctocog alfa PK information from the application program; and (d) outputting, by the one or more electronic devices, the individualized subject PK information, the phanesoctocog alfa popPK model including body weight as a covariate, and the phanesoctocog alfa popPK model not including VWF level or hematocrit level as covariates.

[0014] In some aspects, the disclosure includes a method (e.g., a computer-implemented method) for estimating (e.g., calculating, determining, or providing) individualized target efanesectocog alfa PK information, the method including: (a) receiving, by an application program programmed to implement an efanesectocog alfa popPK model, subject information transmitted by one or more electronic devices; (b) calculating, by the application program, individualized target efanesectocog alfa PK information for efanesectocog alfa using the efanesectocog alfa popPK model and the received information; and (c) transmitting, by a processing device, the calculated individualized target efanesectocog alfa PK information of (b) to one or more electronic devices for output of the information, wherein the efanesectocog alfa popPK model includes body weight as a covariate and the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0015] In some aspects, the disclosure includes a method (e.g., a computer-implemented method) for estimating (e.g., calculating, determining, or providing) personalized efanesectocog alfa PK information, the method comprising: (a) receiving, by one or more electronic devices, information regarding an individual's body weight and (i) a desired increase in plasma factor activity level after a dose, or (ii) a desired dose or a desired dose interval; and (b) transmitting, by a processing device, the information of (a) to an application program, wherein the application is programmed to implement an efanesectocog alfa popPK model. (c) receiving from the web-based server and program individualized targeted phanesoctocog alfa PK information calculated using the phanesoctocog alfa popPK model and the transmitted information of (b); and (d) outputting by one or more electronic devices the calculated individualized targeted phanesoctocog alfa PK information, wherein the phanesoctocog alfa PK model includes body weight as a covariate and the phanesoctocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0016] In some embodiments of the above method, the subject information includes a body weight of the subject.

[0017] In some embodiments of the above methods, the subject information includes the subject's baseline FVIII activity level.

[0018] In some embodiments of the above method, the subject information includes the subject's self-reported race. In some embodiments of the above method, the subject information includes whether the subject self-identifies as Asian.

[0019] In some embodiments of the above methods, the subject provides the subject information. In some embodiments of the above methods, a medical professional provides the subject information.

[0020] In some embodiments of the above methods, the subject information does not include the subject's VWF or hematocrit levels.

[0021] In some embodiments of the above methods, the system is programmed to implement a one-compartment efanesectocog alfa popPK model that includes body weight as a covariate for calculating dosing information, and the efanesectocog alfa popPK model does not include VWF or hematocrit levels as covariates.

[0022] In some embodiments of the above methods, the method also includes selecting a dosing regimen based on the dosing information.

[0023] In some embodiments of the above methods, the method also includes selecting a dosing regimen based on the PK information.

[0024] In some embodiments of the above methods, the methods also include administering efanesoctocog alfa to the subject according to a selected dosing regimen.

[0025] In some embodiments of the above methods, the dosing information comprises estimated or predicted FVIII activity levels over time following administration of efanesectocog alfa.

[0026] In some embodiments of the above methods, the dosing regimen is a prophylactic regimen. In some embodiments of the above methods, the dosing regimen is an on-demand regimen. In some embodiments of the above methods, the dosing regimen is for perioperative management of bleeding.

[0027] In some embodiments of the above methods, the desired treatment outcome information comprises a desired FVIII activity level. In some embodiments of the above methods, the desired FVIII activity level comprises a minimum FVIII activity level between doses.

[0028] In some embodiments of the above methods, the desired FVIII activity level comprises a minimum FVIII activity level at a time point. In some embodiments of the above methods, this time point is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after administration of efanesectocog alfa. In some embodiments, this time point is about 1 week after administration of efanesectocog alfa.

[0029] In some embodiments of the above methods, the phenesoctocog alpha popPK model includes self-reported race as a covariate. In some embodiments of the above methods, the phenesoctocog alpha popPK model includes whether the subject self-reports as Asian as a covariate.

[0030] In some embodiments of the above methods, the subject does not self-identify as Asian. In some embodiments of the above methods, the subject self-identifies as Asian.

[0031] In some embodiments of the above method, the efanesoctocog alfa popPK model is the efanesoctocog alfa popPK model [A].

[0032] In some embodiments, the typical clearance estimate (TVCL) in the efanesectocog alfa popPK model [A] is about 0.433 dL / h, the typical volume estimate (TVV) in the efanesectocog alfa popPK model [A] is about 30.2 dL, the variability in clearance from the central compartment (η1) in the efanesectocog alfa popPK model [A] is about 0.0354, and / or the variability in the volume of the central compartment (η2) in the efanesectocog alfa popPK model [A] is about 0.0209. In some embodiments, the typical clearance estimate (TVCL) in the efanesectocog alfa popPK model [A] is about 0.433 dL / h, the typical volume estimate (TVV) in the efanesectocog alfa popPK model [A] is about 30.2 dL, the variability in clearance from the central compartment (η1) in the efanesectocog alfa popPK model [A] is about 0.0354, and the variability in the volume of the central compartment (η2) in the efanesectocog alfa popPK model [A] is about 0.0209. In some embodiments, the typical clearance estimate (TVCL) in the efanesectocog alfa popPK model [A] is 0.433 dL / h, the typical volume estimate (TVV) in the efanesectocog alfa popPK model [A] is 30.2 dL, the variability in clearance from the central compartment (η1) in the efanesectocog alfa popPK model [A] is 0.0354, and the variability in the volume of the central compartment (η2) in the efanesectocog alfa popPK model [A] is 0.0209.

[0033] In some embodiments of the methods disclosed herein, the electronic device is a digital pen, a smartphone, a tablet computer, a personal digital assistant, a handheld computer, a laptop computer, a scanner, a camera, and / or a fax machine.

[0034] Also included is a method (e.g., a computer-implemented method) of treating hemophilia A in a subject in need thereof, comprising administering to the subject a dose regimen selected according to any one of the above methods.

[0035] Also disclosed are systems including a processor configured to provide dosing or PK information according to any one of the above methods. In some embodiments, the system is a network-based system. In some embodiments, the system is a web-based system.

[0036] In some embodiments, the system is programmed to implement a one-compartment efanesectocog alfa popPK model with linear elimination that includes body weight as a covariate for calculating dosing information, and the efanesectocog alfa popPK model does not include VWF or hematocrit levels as covariates.

[0037] In some embodiments, the system is programmed to implement a one-compartment efanesectocog alfa popPK model with linear elimination that includes body weight as a covariate for calculating individualized subject efanesectocog alfa PK information, and the efanesectocog alfa popPK model does not include VWF or hematocrit levels as covariates.

[0038] In some aspects, the disclosure includes a data processing device, device, or system comprising a processor configured to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0039] In some embodiments of the above data processing apparatus, device or system, the efanesoctocog alpha popPK model includes self-reported race as a covariate.

[0040] In some embodiments of the above data processing apparatus, device or system, the effanesoctocog alpha popPK model includes as a covariate whether the subject self-reports as Asian.

[0041] In some embodiments of any of the above data processing devices, devices or systems, the data processing device, device or system comprises a smartphone, a tablet computer, a personal digital assistant, a handheld computer, a laptop computer or a smartwatch.

[0042] In some embodiments of any of the above data processing apparatuses, devices or systems, the data processing apparatuses, devices or systems comprise a smartphone. In some embodiments of any of the above data processing apparatuses, devices or systems, the data processing apparatuses, devices or systems comprise a smartwatch.

[0043] In some embodiments of any of the above data processing apparatuses, devices or systems, the processor is configured to implement the effanesoktocog alpha popPK model [A].

[0044] Also disclosed is a computer program comprising instructions that, when the program is executed by a computer, cause the computer to perform any one of the methods described above.

[0045] In some aspects, the disclosure includes a computer program comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0046] In some embodiments of the computer program, the phenesoctocog alpha popPK model includes self-reported race as a covariate. In some embodiments of the computer program, the phenesoctocog alpha popPK model includes whether the subject self-reports as Asian as a covariate.

[0047] In some embodiments of the above computer program, the efanesoctocog alpha popPK model is the efanesoctocog alpha popPK model [A].

[0048] In some embodiments, the computer program is accessible via a web server or network server.

[0049] Also disclosed is a computer-readable medium containing instructions that, when executed by a computer, cause the computer to perform any one of the above methods.

[0050] In some aspects, the disclosure includes a computer-readable medium comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0051] In some embodiments of the computer-readable medium, the phenesoctocog alpha popPK model includes self-reported race as a covariate. In some embodiments of the computer-readable medium, the phenesoctocog alpha popPK model includes whether the subject self-reports as Asian as a covariate.

[0052] In some embodiments of the above computer-readable medium, the efanesoctocog alpha popPK model is the efanesoctocog alpha popPK model[A].

[0053] In some embodiments, the computer readable medium is accessible via a web server or network server.

[0054] Included herein are methods for determining (e.g., calculating or providing an estimate of) chimeric protein dosing information for an individual subject, wherein the chimeric protein comprises (i) a factor VIII (FVIII) protein and (ii) a von Willebrand factor (VWF) fragment comprising the D' domain of VWF and the D3 domain of VWF.

[0055] In some embodiments, the method includes receiving subject-specific information and calculating chimeric protein dosing information using a software-based system, the system being programmed to implement a one-compartment chimeric protein popPK model, the chimeric protein popPK model including body weight as a covariate, and the chimeric protein popPK model not including VWF level or hematocrit level as a covariate.

[0056] In some embodiments, the method includes outputting, by the software-based system, dosing information for the subject. In some embodiments, the method includes outputting, by the software-based system, a suggested dosing regimen. In some embodiments, desired treatment outcome information is also received.

[0057] The present disclosure provides a method for estimating personalized chimeric protein dosing information for a subject, wherein the chimeric protein comprises (i) a factor VIII (FVIII) protein and (ii) a von Willebrand factor (VWF) fragment comprising the D' domain of VWF and the D3 domain of VWF.

[0058] In some embodiments, the method includes: (a) receiving subject information and / or desired treatment outcome information by a processing device using an application program programmed to operate with a chimeric protein popPK model, wherein the received information is transmitted by one or more electronic devices; (b) calculating personalized chimeric protein dosing information using at least a software-based system using the chimeric protein popPK model and the received information; and (c) transmitting the calculated personalized chimeric protein dosing information of (b) to the one or more electronic devices for outputting the information, wherein the chimeric protein popPK model includes body weight as a covariate, and wherein the chimeric protein popPK model does not include VWF level or hematocrit level as covariates.

[0059] In some embodiments, the method includes (a) receiving, by one or more electronic devices, subject information and / or desired treatment outcome information; (b) transmitting, by a processing device, the subject information and / or desired treatment outcome information to an application program, wherein the application is programmed to implement a chimeric protein popPK model; (c) receiving from the application program personalized chimeric protein dosing information calculated using the chimeric protein popPK model and the transmitted information of (b); and (d) outputting, by the one or more electronic devices, the personalized chimeric protein dosing information, wherein the chimeric protein popPK model includes body weight as a covariate and the chimeric protein popPK model does not include VWF level or hematocrit level as a covariate.

[0060] Also included herein is a method for estimating PK information of a personalized target chimeric protein, the chimeric protein comprising (i) a factor VIII (FVIII) protein and (ii) a von Willebrand factor (VWF) fragment comprising the D' domain of VWF and the D3 domain of VWF.

[0061] In some embodiments, the method includes: (a) receiving subject information by a software-based system including a chimeric protein popPK model; (b) estimating, by the software-based system, personalized subject chimeric protein PK information using the chimeric protein popPK model and the received information; and (c) outputting, by the software-based system, the personalized subject chimeric protein PK information, wherein the chimeric protein popPK model includes body weight as a covariate and the chimeric protein popPK model does not include VWF level or hematocrit level as a covariate.

[0062] In some embodiments, the method includes (a) receiving subject information by one or more electronic devices; (b) transmitting, by a processing device, the subject information to an application program, wherein the application is programmed to implement a chimeric protein popPK model, and the application program uses the chimeric protein popPK model and the transmitted information to generate and transmit personalized subject chimeric protein PK information; (c) receiving the personalized subject chimeric protein PK information from the application program; and (d) outputting, by the one or more electronic devices, the personalized subject PK information, wherein the chimeric protein popPK model includes body weight as a covariate, and wherein the chimeric protein popPK model does not include VWF level or hematocrit level as a covariate.

[0063] In some embodiments, the method includes: (a) receiving subject information by an application program programmed to implement a chimeric protein popPK model, wherein the received information is transmitted by one or more electronic devices; (b) calculating, by the application program, personalized subject chimeric protein PK information for the chimeric protein using the chimeric protein popPK model and the received information; and (c) transmitting, by a processing device, the calculated personalized subject chimeric protein PK information of (b) to the one or more electronic devices for outputting the information, wherein the chimeric protein popPK model includes body weight as a covariate, and wherein the chimeric protein popPK model does not include VWF level or hematocrit level as covariates.

[0064] In some embodiments, the method includes: (a) receiving, by one or more electronic devices, information regarding an individual's body weight and (i) a desired increase in plasma factor activity level after a dose, or (ii) a desired dose or a desired dose interval; (b) transmitting, by a processing device, the information of (a) to an application program, wherein the application is programmed to implement a chimeric protein popPK model; (c) receiving, from a web-based server and program, personalized target chimeric protein PK information calculated using the chimeric protein popPK model and the transmitted information of (b); and (d) outputting, by the one or more electronic devices, the calculated personalized target chimeric protein PK information, wherein the chimeric protein popPK model includes body weight as a covariate, and wherein the chimeric protein popPK model does not include VWF level or hematocrit level as a covariate.

[0065] In some embodiments, the subject information includes a body weight of the subject.

[0066] In some embodiments, the subject information includes the subject's baseline FVIII activity level.

[0067] In some embodiments, the subject information includes the subject's self-reported race, hi some embodiments, the subject information includes whether the subject self-identifies as Asian.

[0068] In some embodiments, the subject provides the subject information. In some embodiments, a medical professional provides the subject information.

[0069] In some embodiments, the subject information does not include the subject's VWF or hematocrit levels.

[0070] In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model that includes body weight as a covariate for calculating dosing information, wherein the chimeric protein popPK model does not include VWF or hemoctocrit levels as covariates. In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model with linear elimination that includes body weight as a covariate for calculating dosing information, wherein the chimeric protein popPK model does not include VWF or hemoctocrit levels as covariates. In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model that includes body weight as a covariate for calculating individualized subject PK information, wherein the chimeric protein popPK model does not include VWF or hemoctocrit levels as covariates. In some embodiments, the system is programmed to implement a one-compartment chimeric protein popPK model with linear elimination that includes body weight as a covariate for calculating individualized subject PK information, wherein the chimeric protein popPK model does not include VWF or hemoctocrit levels as covariates.

[0071] In some embodiments, the method further comprises selecting a dosing regimen based on the dosing information. In some embodiments, the method further comprises selecting a dosing regimen based on the PK information. In some embodiments, the method further comprises administering the chimeric protein to the subject according to the selected dosing regimen.

[0072] In some embodiments, the dosing information includes estimated or predicted FVIII activity levels over time following administration of the chimeric protein.

[0073] In some embodiments, the dosing regimen is a prophylactic regimen. In some embodiments, the dosing regimen is an on-demand regimen. In some embodiments, the dosing regimen is for perioperative management of bleeding.

[0074] In some embodiments, the desired treatment outcome information includes a desired FVIII activity level. In some embodiments, the desired FVIII activity level includes a minimum FVIII activity level between doses. In some embodiments, the desired FVIII activity level includes a minimum FVIII activity level at a time point. In some embodiments, this time point is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after administration of the chimeric protein. In some embodiments, this time point is about 1 week after administration of the chimeric protein.

[0075] In some embodiments, the chimeric protein popPK model includes self-reported race as a covariate. In some embodiments, the chimeric protein popPK model includes whether the subject self-reports as Asian as a covariate. In some embodiments, the subject does not self-report as Asian. In some embodiments, the subject self-reports as Asian.

[0076] Included herein are methods of treating hemophilia A in a subject in need thereof, comprising administering to the subject a dose regimen selected according to the methods disclosed herein.

[0077] Also provided is a device or system including a processor configured to provide dosing or PK information according to the methods disclosed herein.

[0078] The present disclosure further provides a data processing device, device, or system comprising a processor configured to implement a one-compartment chimeric protein popPK model, wherein the chimeric protein popPK model includes body weight as a covariate, and wherein the chimeric protein popPK model does not include VWF level or hematocrit level as a covariate. In some embodiments, the chimeric protein popPK model includes self-reported race as a covariate. In some embodiments, the chimeric protein popPK model includes whether the subject self-reports as Asian as a covariate. In some embodiments, the data processing device, device, or system comprises a smartphone, tablet computer, personal digital assistant, handheld computer, laptop computer, or smartwatch. In some embodiments, the data processing device, device, or system comprises a smartphone and / or a smartwatch.

[0079] The present specification also includes a computer program comprising instructions that, when executed by a computer, cause the computer to perform a method disclosed herein, e.g., a method comprising a chimeric protein popPK model, wherein the chimeric protein popPK model includes body weight as a covariate but does not include VWF level or hematocrit level as a covariate. In some embodiments, the chimeric protein popPK model includes self-reported race as a covariate. In some embodiments, the chimeric protein popPK model includes whether the subject self-reports as Asian as a covariate.

[0080] Provided herein is a computer-readable medium comprising instructions, when executed by a computer, that cause the computer to perform a method disclosed herein, e.g., a method comprising a chimeric protein popPK model, wherein the chimeric protein popPK model includes body weight as a covariate but does not include VWF level or hematocrit level as a covariate. In some embodiments, the chimeric protein popPK model includes self-reported race as a covariate. In some embodiments, the chimeric protein popPK model includes whether the subject self-reports as Asian as a covariate.

[0081] In some embodiments, the FVIII polypeptide has a deletion of amino acids 746 to 1648, corresponding to mature FVIII (SEQ ID NO: 7), and the first ELNN polypeptide is inserted within the FVIII polypeptide immediately downstream of amino acid 745, corresponding to mature FVIII (SEQ ID NO: 7), and the first ELNN polypeptide comprises an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO: 8.

[0082] In some embodiments, the VWF fragment comprises the D' domain of VWF and the D3 domain of VWF, the VWF fragment is mutated to replace cysteines involved in VWF dimerization with alanines, the second ELNN polypeptide comprises an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO: 9, and the linker comprises an amino acid sequence that is at least about 90% identical to the amino acid sequence of SEQ ID NO: 10.

[0083] In some embodiments, the first ELNN polypeptide comprises the sequence of SEQ ID NO:8 and the second ELNN polypeptide comprises the amino acid sequence of SEQ ID NO:9.

[0084] In some embodiments, the chimeric protein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises an amino acid sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 3, and the second polypeptide comprises an amino acid sequence that is at least about 95% identical to the amino acid sequence of SEQ ID NO: 6, and wherein the first polypeptide and the second polypeptide are covalently linked by two disulfide bonds between the first Fc region and the second Fc region.

[0085] In some embodiments, the chimeric protein comprises a first polypeptide and a second polypeptide, wherein the first polypeptide comprises the amino acid sequence set forth as SEQ ID NO:3 and the second polypeptide comprises the amino acid sequence set forth as SEQ ID NO:6, and wherein the first polypeptide and the second polypeptide are covalently linked by two disulfide bonds between the first Fc region and the second Fc region. [Brief explanation of the drawings]

[0086] [Figure 1] 1 is a visual representation of a software-based system that can be used in the methods disclosed herein. [Figure 2] 1 is a visual representation of an exemplary network-based system that can be used in accordance with the methods disclosed herein. [Figure 3] 4 shows a schematic diagram of an exemplary computing system 400. [Figure 4] FIG. 1 is a graph showing efanesoctocog alfa individual clearance (dL / h) at baseline VWF levels (IU / dL) in adult and adolescent patients. [Figure 5]1 is a graph showing simulated steady-state FVIII activity over time using the efanesectocog alfa population PK model [A] (50 IU / kg) in patients aged 12 years and older based on clinical data from a one-stage clotting assay. Also shown is the observed FVIII activity from the clinical data. The solid line is the simulated median FVIII activity (IU / dL). The dashed lines are simulated at the 5th and 95th percentiles. [Figure 6A] Graph showing baseline-corrected FVIII activity time profiles from adult / adolescent study EFC16293 on Day 1. Data shown for all patients. LLOQ=1 IU / dL [Figure 6B] Graph showing baseline-corrected FVIII activity time profiles from adult / adolescent study EFC16293 at day 1 (solid line) and week 26 (dashed line). Data is shown for patients in the sequential arm only. [Figure 7] Correlations between four continuous covariates at baseline are shown. WTKGB is baseline weight (median 78.3, excluding EFC16295). BH is baseline race (median 43, excluding EFC16295). BVWF is baseline VWF (median 112, excluding EFC16295). [Figure 8A-8B] 8A and 8B are graphs showing population predictions (PRED) (FIG. 8A) and individual predictions (IPRED) (FIG. 8B) versus observed values ​​(DV; data values) of single-stage FVIII activity using the efanesectocog alfa population PK model [A]. The black line is the unity line. The gray line is the loess smoothed line. For the population predictions in FIG. 8A, R2=0.92. For the individual predictions in FIG. 8B, R2=0.97. [Figure 9]

[0023] Figure 1 is a set of graphs demonstrating the performance of the efanesectocog alfa population PK model [A] using visual predictive testing (VPC). Open circles represent observed data. Solid lines represent model simulated medians. Dashed lines represent model simulated 5th and 95th percentiles. Shading around each dashed line represents the 90% CI around the simulated 5th and 95th percentiles. Shading around each solid line represents the 90% CI around the simulated median. [Figures 10A-10B] Figure 10 demonstrates PRED (Figure 10A) and IPRED (Figure 10B) vs. DV for surgery using the efanesectocog alfa population PK model [A]. The gray line is the line of unity. R2 is shown as the black line, which is the regression line between observed and predicted. [Figure 11] 1 is a set of graphs showing the distribution of steady-state Ctrough, Cmaxss and time to 40 IU / dL FVIII activity levels across the population. [Figure 12] 1 is a set of graphs showing the distribution of steady-state Ctrough, Cmaxss and time to 40 IU / dL FVIII activity level across non-Asian and Asian populations. [Figure 13] 1 is a graph showing OSC FVIII activity over time for major surgery and major bleeding for patients 6 years of age and younger. Gray solid line: simulated median for 30 IU / kg dose. Circular gray line: simulated median for 50 IU / kg dose. Black solid lines: simulated 5th and 95th percentiles. Dashed lines indicate OSC activity at 80 IU / kg and 40 IU / kg. [Figure 14] 1 is a graph showing simulated FVIII activity in a simulated adult and adolescent population following efanesectocog alfa at a dose of 50 IU / kg followed by 30 IU / kg every 3 days up to day 14. [Figure 15] 1 is a graph showing simulated OSC FVIII activity over time for all age groups. DETAILED DESCRIPTION OF THE INVENTION

[0087] With the advent of extended half-life replacement products, treatment goals have now expanded beyond targeting a low annualized bleeding rate (ABR) to include long-term outcomes associated with high, sustained plasma FVIII activity levels, such as long-term joint protection. Evanesoctocog alfa circulates independently of endogenous von Willebrand factor (VWF) and provides high, sustained FVIII activity (see, e.g., Chhabra, et al. Blood. 2020;135(17):1484-1496 and Konkle et al., N Engl J Med 2020;383:1018-1027 (wherein efanesoctocog alfa is referred to as BIVV001), the entire contents of each of which are incorporated herein by reference for all purposes).

[0088] The present disclosure provides, among other things, treatment methods and software-based systems for estimating individualized subject efanesectocog alfa PK information for the treatment of hemophilia A. Included, for example, are methods for estimating individualized subject efanesectocog alfa PK information using a software-based system. In some embodiments, the software-based system applies an efanesectocog alfa population PK model [A] to estimate dosing information for subjects receiving efanesectocog alfa as FVIII replacement therapy.

[0089] The present disclosure provides, inter alia, treatment methods and software-based systems for estimating or quantifying the risk of bleeding with high sustained FVIII activity. In some embodiments, the software-based system can apply a pharmacokinetic / pharmacodynamic model of the efanesectocog alfa population to quantify the risk of bleeding with high sustained FVIII activity compared to standard of care.

[0090] definition The term "about" is used herein to mean approximately, roughly, around, or within a range thereof. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" can modify a numerical value above and below the stated value by, for example, a 10 percent variance above or below (higher or lower). In some embodiments, the term indicates a ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, or ±0.01% deviation from the stated numerical value. In some embodiments, "about" indicates a ±10% deviation from the stated numerical value. In some embodiments, "about" indicates a ±5% deviation from the stated numerical value. In some embodiments, "about" indicates a ±4% deviation from the stated numerical value. In some embodiments, "about" indicates a ±3% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±2% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±1% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.9% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.8% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.7% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.6% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.5% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.4% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.3% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.1% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.05% deviation from the indicated numerical value. In some embodiments, "about" indicates a ±0.01% deviation from the indicated numerical value.

[0091] Whenever an embodiment is described herein in the language of "comprising," it is understood that otherwise similar embodiments described in the terms "consisting of" and / or "consisting essentially of" are also provided.

[0092] As used herein in reference to hemophilia A, the term "prophylactic treatment" refers to the upfront administration of a therapy for the treatment of hemophilia A, where such treatment is intended to prevent or reduce the severity of one or more symptoms of hemophilia A, e.g., bleeding episodes, such as one or more spontaneous bleeding episodes, and / or joint damage. To prevent or reduce such symptoms, e.g., bleeding episodes and progression of joint disease, patients with hemophilia A may receive regular infusions of a clotting factor (e.g., efanesectocog alfa) as part of a prophylactic treatment regimen.

[0093] The terms "on-demand treatment" or "episodic treatment" refer to the administration of FVIII replacement therapy (such as efanesectocog alfa) "as needed" in response to a symptom of hemophilia A, such as a bleeding episode (such as a spontaneous bleeding episode or a traumatic bleeding episode), or before an activity that may cause bleeding. In some embodiments, on-demand treatment can be administered to a subject when bleeding begins, such as after an injury, or when bleeding is expected, such as before surgery. In some embodiments, on-demand treatment can be administered before an activity that increases the risk of bleeding, such as contact sports. In some embodiments, on-demand treatment can be administered to a subject receiving prophylactic treatment, for example, when a replacement FVIII replacement protein dose is administered to treat a bleeding episode or before strenuous activity. In some embodiments, on-demand treatment is administered as a single dose. In some embodiments, on-demand treatment is administered as a first dose, followed by one or more booster doses. In some embodiments, the on-demand regimen is for perioperative management of bleeding.

[0094] In some embodiments, a bleeding episode begins at the first sign of bleeding and ends 72 hours after the last treatment of bleeding, wherein any episode of bleeding or injection at the same location within 72 hours is considered the same bleeding episode. See Blanchette V. (2006) Haemophilia 12:124-7. In some embodiments, any injection to treat a bleeding episode administered more than 72 hours after the preceding injection is considered the first injection to treat a new bleeding episode at the same location. In some embodiments, any bleeding at a different location is considered a separate bleeding episode, regardless of the time since the last injection.

[0095] The methods provided herein can be applied to subjects in need of preventative or episodic / on-demand treatment. In some embodiments, the subject in need of preventative or episodic / on-demand treatment is suffering from hemarthrosis, muscle bleeding, oral bleeding, bleeding into muscles, oral hemorrhage, trauma, head trauma, gastrointestinal bleeding, intracranial bleeding, intraperitoneal bleeding, intrathoracic bleeding, fracture, central nervous system bleeding, retropharyngeal bleeding, retroperitoneal bleeding, and iliopsoas sheath bleeding. In some embodiments, the subject requires treatment for surgery, including, for example, surgical prophylaxis or perioperative management. In some embodiments, the surgery is minor or major surgery. Exemplary surgical procedures include tooth extraction, tonsillectomy, inguinal herniotomy, synovectomy, craniotomy, bone fixation, trauma surgery, intracranial surgery, intraperitoneal surgery, intrathoracic surgery, joint replacement surgery (e.g., total knee replacement, hip replacement, etc.), cardiac surgery, and cesarean section.

[0096] As used herein in relation to hemophilia A, "treat" and "treating" include, for example, reducing the severity of hemophilia A; ameliorating one or more symptoms associated with hemophilia A; providing a beneficial effect to a subject with hemophilia A without necessarily curing hemophilia A; and / or preventing one or more symptoms associated with hemophilia A.

[0097] In some embodiments, treating hemophilia A includes preventing one or more symptoms of hemophilia A (such as spontaneous bleeding). In some embodiments, treating hemophilia A includes reducing the likelihood of a bleeding episode or reducing the severity of a bleeding episode. In some embodiments, treatment is prophylactic treatment. In some embodiments, treatment is on-demand treatment. In some embodiments, treatment includes reducing the frequency of one or more symptoms of hemophilia A, such as spontaneous or uncontrollable bleeding episodes.

[0098] As used herein, the term "perioperative management" refers to the use of efanesectocog alfa before, concurrently with, or after a surgical procedure, e.g., surgery. Use for the "perioperative management" of one or more bleeding episodes includes pre-operative (i.e., pre-operative), intra-operative (i.e., intra-operative), or post-operative (i.e., post-operative) surgical prophylaxis to prevent one or more hemorrhages or bleeding episodes, or to reduce or inhibit spontaneous and / or uncontrollable bleeding episodes before, during, and after surgery.

[0099] As used herein, a "baseline" plasma FVIII level is the lowest measured plasma FVIII level in a subject before administration of a dose. In some embodiments, activity above the pre-dose baseline can be considered residual FVIII activity from previous treatment, can decay over time using the half-life of the previous treatment, and can be subtracted from the PK data after administration of efanesectocog alfa. In some embodiments, the baseline FVIII activity level is the level of FVIII activity in the blood (e.g., as assessed in plasma) of a patient with hemophilia A without treatment.

[0100] The terms "patient" and "subject" are used interchangeably herein and refer to a human. A subject may include, for example, an individual diagnosed with hemophilia A and prone to idiopathic and / or uncontrolled bleeding episodes. A subject may also include an individual at risk for one or more uncontrolled bleeding episodes before a particular activity, such as surgery, sporting activity, or any strenuous activity. In some embodiments, the subject has a baseline FVIII activity of less than 0.5%, less than 1%, less than 2%, less than 2.5%, less than 3%, or less than 4%. In some embodiments, the subject has severe hemophilia A, defined as an endogenous FVIII activity of less than 1 IU / dL (less than 1%). In some embodiments, the subject does not have a coagulation disorder other than hemophilia A.

[0101] As used herein, the terms "ELNN polypeptide" and "ELNN" are synonymous and refer to an extended polypeptide comprising a non-naturally occurring, substantially non-repetitive sequence (e.g., a polypeptide motif) composed primarily of small, hydrophilic amino acids, with a sequence that has little or no secondary or tertiary structure under physiological conditions. Such extended polypeptides include unstructured, hydrophilic polypeptides comprising repeating motifs of the six naturally occurring amino acids (G, A, P, E, S, and / or T). In some embodiments, the ELNN polypeptide comprises multiple motifs of the six naturally occurring amino acids (G, A, P, E, S, T), where the motifs comprise combinations of the same or different motifs. When linked to a VWF fragment or FVIII sequence of the present disclosure to create a chimeric polypeptide or protein, the ELNN polypeptide can confer certain desirable pharmacokinetic, physicochemical, and pharmaceutical properties. Such desirable properties include, but are not limited to, enhanced pharmacokinetic parameters and solubility properties. ELNN polypeptides are known in the art, and non-limiting descriptions of and examples of ELNN polypeptides known as XTEN polypeptides are available in Schellenberger et al., (2009) Nat Biotechnol 27(12):1186-90; Brandl et al., (2020) Journal of Controlled Release 327:186-197; and Radon et al., (2021) Advanced Functional Materials 31, 2101633 (pages 1-33), the entire contents of each of which are incorporated herein by reference.

[0102] As used herein, a "software-based system" refers to an algorithm or set of algorithms that can be implemented by a processing device. A software-based system may be implemented in software, including but not limited to firmware, resident software, microcode, etc., and may take the form of a computer program product accessible from a computer-usable or computer-readable medium that provides program code for use by or in connection with a computer or any instruction execution system. For purposes of this description, a computer-usable or computer-readable medium may be any apparatus that can contain, store, communicate, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device. The medium may be an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system (or apparatus or device) or a propagation medium. Examples of computer-readable media include semiconductor or solid-state memory, magnetic tape, removable computer diskettes, random access memory (RAM), read-only memory (ROM), rigid magnetic disks, and optical disks, including compact disc read-only memory (CD-ROM), compact disc read / write (CD-R / W), and DVD. Non-limiting examples of software-based systems include network-based systems and web-based systems.

[0103] As used herein, the term "processing device" refers to a data processing system suitable for storing and / or executing program code for implementing a software-based system, and may include at least one processor coupled directly or indirectly to memory elements via a system bus. A processor, which is an electronic circuit that executes instructions constituting program code, may be instantiated by a microprocessor, microcontroller, multi-core processor, array of processors, or vector processor. Memory elements may include local memory used during the actual execution of the program code, mass storage devices, and cache memories that provide temporary storage of at least some of the program code to reduce the number of times the code must be retrieved from mass storage devices during execution. Input / output or I / O devices (including, but not limited to, keyboards, displays, pointing devices, touchscreens, audio, etc.) may be coupled to the system directly or through intervening I / O controllers. Network adapters may also be coupled to the system to enable the processing device to be coupled to other processing devices or remote printers or storage devices via intervening private or public networks. Modems, cable modems, and Ethernet cards are just a few of the currently available types of network adapters. The processing device may also be a shared data processing system, such as a network-based (e.g., web-based) server system accessible over a network, such as the Internet, that can access and execute program code to implement a software-based system.

[0104] Description of Ephanesoctocog Alpha Efanesoctocog alfa is described in Chhabra et al., Blood 2020;135(17):1484-1496, Konkle et al., N Engl J Med 2020;383:1018-1027, and the International Nonproprietary Names for Pharmaceutical Substances (INN) WHO Drug Information, 2019, Vol. 33, No. 4, pp. 828-30, the entire contents of each of which are incorporated herein by reference. Efanesoctocog alfa temporarily replaces the defective FVIII required for effective hemostasis in FVIII-deficient patients. Efanesoctocog alfa comprises a first polypeptide comprising the amino acid sequence of SEQ ID NO: 3 covalently linked to a second polypeptide comprising the amino acid sequence of SEQ ID NO: 6, the first and second polypeptides being covalently linked to each other via a disulfide bond. Evanesoctocog alfa can be produced by recombinant DNA technology, for example, in a human embryonic kidney (HEK) cell line. For example, the cell line can express the rFVIIIFc-ELNN polypeptide (SEQ ID NO: 1), the rVWF-ELNN-Fc polypeptide (SEQ ID NO: 4), and the soluble PACE enzyme. Non-limiting examples of nucleotide sequences encoding the rFVIIIFc-ELNN polypeptide (SEQ ID NO: 2) and the rVWF-ELNN-Fc polypeptide (SEQ ID NO: 5) can be found in Table 7 below. The amino acid sequences of the rFVIIIFc-ELNN polypeptide without the signal peptide (SEQ ID NO: 3) and the rVWF-ELNN-Fc polypeptide without the signal peptide or the D1D2 portion of VWF (SEQ ID NO: 6) can be found in Table 7 below.

[0105] In some embodiments for subjects receiving prophylactic treatment with efanesectocog alfa, the methods disclosed herein can be used to determine individualized subject information (e.g., the subject's plasma FVIII level at a particular time point or set of time points). Based on this individualized subject information, the dose and / or dose interval of efanesectocog alfa can be adjusted to achieve individualized treatment goals, such as minimum plasma FVIII levels (e.g., trough).

[0106] In some embodiments, for subjects receiving on-demand treatment with efanesectocog alfa, if the subject's bleeding is not or insufficiently controlled after administration of efanesectocog alfa at the initial recommended dose and dose interval, the methods disclosed herein can be used to determine individual subject dosing information. Based on this individual subject dosing information, the dose and / or dose interval of efanesectocog alfa can be adjusted to achieve improved bleeding control.

[0107] In some embodiments, the methods disclosed herein can be used to estimate a subject's minimum FVIII level between doses.

[0108] If clinically indicated, the subject's plasma can be monitored for FVIII activity levels, for example, in a one-stage clotting assay, to ensure that adequate FVIII levels are achieved and maintained. FVIII activity can be measured by any method known in the art. Many tests are available to assess the function of the coagulation system, including activated partial thromboplastin time (aPTT) tests, chromogenic assays, ROTEM assays, prothrombin time (PT) tests (also used to determine the INR), fibrinogen tests (often by the Clauss method), platelet counts, platelet function tests (often by PFA-100), TCT, bleeding time, mixing tests (whether abnormalities are corrected when the subject's plasma is mixed with normal plasma), coagulation factor assays, antiphospholipid antibodies, D-dimers, genetic tests (e.g., factor V Leiden, prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), multifaceted platelet function tests, thromboelastography (TEG or Sonoclot), thromboelastometry (TEM®, e.g., ROTEM®), or euglobulin lysis time (ELT).

[0109] The aPTT test is a figure of merit that measures the efficacy of the "intrinsic" coagulation pathway (also called the contact activation pathway) and the general coagulation pathway. This test is commonly used to measure the clotting activity of commercially available recombinant coagulation factors, such as FVIII. It is typically used in conjunction with prothrombin time (PT), which measures the extrinsic pathway. (See, e.g., Kamal et al., Mayo Clin Proc., 82(7):864-873 (2007)). In some embodiments, an assay is used to test aPTT, where FVIII activity is measured using Dade Actin FSL Activated PTT Reagent (Siemens Healthcare Diagnostics) on a BCS XP analyzer (Siemens Healthcare Diagnostics).

[0110] In some embodiments, the aPTT assay can also be used to assess the efficacy of a chimeric polypeptide before administration to a subject. (Hubbard AR, et al. J Thromb Haemost 11:988-9 (2013)) In some embodiments, the aPTT assay can be further used in conjunction with any of the assays described herein, either before or after administration to a subject.

[0111] In some embodiments, the models provided herein provide FVIII activity calculations and information corresponding to activity measured by an aPTT test. For example, the efanesectocog alfa popPK model [A] provides FVIII activity calculations and information corresponding to activity measured by an aPTT test.

[0112] ROTEM analysis provides information on the overall dynamics of hemostasis: clotting time, clot formation, clot stability, and lysis. The various parameters of thromboelastometry depend on the activity of the plasma coagulation system, platelet function, fibrinolysis, or many factors that affect their interactions. This assay can provide a complete picture of secondary hemostasis.

[0113] The chromogenic assay mechanism is based on the principle of the blood coagulation cascade, in which activated FVIII promotes the conversion of factor X to factor Xa in the presence of activated factor IX, phospholipids, and calcium ions. Factor Xa activity is assessed by hydrolysis of the factor Xa-specific p-nitroanilide (pNA) substrate. The initial release rate of p-nitroaniline, measured at 405 nM, is directly proportional to factor Xa activity and, therefore, FVIII activity in the sample. In some embodiments, the chromogenic assay is the BIOPHEN FVIII:C assay (Hyphen Biomed, Aubers-sur-Oise, France). In some embodiments, the chimeric polypeptide comprising a FVIII polypeptide has FVIII activity comparable to that of a chimeric polypeptide comprising a mature FVIII polypeptide or a BDD FVIII polypeptide (e.g., recombinate®, KOGENATE FS®, HELIXATE FS®, XYNTHA / REFACTO AB®, HEMOFIL-M®, MONARCM®, MONOCLATE-P®, HUMATE-P®, ALPHANATE®, KOATE-DVI®, AFSTYLA®, HYATE:C®).

[0114] In some embodiments, a chromogenic assay can also be used to assess the efficacy of a chimeric polypeptide prior to administration to a subject. (Hubbard AR, et al. J Thromb Haemost 11:988-9 (2013)) A chromogenic assay can also be used in conjunction with any of the assays described herein, either prior to or after administration to a subject.

[0115] Target medication information For most currently available FVIII replacement therapies, the FVIII dose required for each subject is calculated using the following formula: Number of Factor VIII units needed (IU) = body weight (kg) x Desired FVIII increase (IU / dL or % of normal x 0.5 (IU / kg / IU / dL)) [B]

[0116] This calculation provides a general estimate of a subject's dosing requirements based on body weight and desired increase in FVIII activity level as subject-specific variables.

[0117] Disclosed herein is a model [A] for determining or estimating dosing information for subjects with hemophilia A receiving FVIII replacement therapy with efanesectocog alfa. The efanesectocog alfa popPK model [A] is represented as follows:

number

[0118] Investigations into covariates affecting FVIII activity have historically focused on VWF concentration. However, VWF concentration was not found to be a covariate in the efanesectocog alfa popPK data and model disclosed herein. Without being bound by any scientific theory, it is noted that efanesectocog alfa clearance is independent of endogenous VWF. Hematocrit was also not found to be a covariate.

[0119] For the efanesoctocog alfa popPK model disclosed herein, clearance from the central compartment (CL) and the volume of the central compartment (V) were found to be dependent on body weight. Asian ethnicity was also identified as a covariate on CL.

[0120] In some embodiments, the race is the subject's self-reported race. For example, the subject may self-report from a set of possible options that includes the option "Asian." In some embodiments, if the subject decides not to report their race, the subject is considered non-Asian for purposes of the model. In some embodiments, if self-reported race information is not collected or cannot be collected, the subject is considered non-Asian for purposes of the model. In some embodiments, a subject who self-reports as Asian self-identifies as being of East Asian descent. In some embodiments, a subject who self-reports as Asian self-identifies as being of Southeast Asian descent. In some embodiments, a subject who self-reports as Asian self-identifies as being of Central Asian descent. In some embodiments, a subject who self-reports as Asian self-identifies as being of North Asian descent. In some embodiments, a subject who self-reports as Asian self-identifies as being of West Asian descent. In some embodiments, a subject self-identifies as being of East Asian descent. In some embodiments, a subject self-identifies as being of South Asian descent. In some embodiments, a subject self-identifies as being of Central Asian descent. In some embodiments, a subject self-identifies as being of Southeast Asian descent. In some embodiments, the subject self-identifies as being of West Asian descent.

[0121] Some embodiments comprise administering a dose of efanesectocog alfa to a human subject in need thereof at a dosing interval, wherein the dose and / or dosing interval is identified using the subject's body weight and / or self-reported race, but not the subject's VWF or hematocrit levels. The present disclosure provides a method of administering a dose of efanesectocog alfa to a human subject in need thereof at a dosing interval, wherein the dose and / or dosing interval is identified by applying the efanesectocog alfa model [A] disclosed herein.

[0122] The efanesectocog alfa model [A] disclosed herein can be used to determine individual subject dosing information to assess and / or confirm a subject's treatment goals. This individual subject dosing information can be used to determine the dose and / or dosing interval of efanesectocog alfa in future treatments. Treatment goals can include, for example, higher plasma FVIII levels over an extended period of time.

[0123] In some embodiments, the therapeutically effective dose of efanesectocog alfa is about 50 IU / kg. In some embodiments, a subject is administered a dose of about 50 IU / kg once a week. In some embodiments, a subject is administered a dose of about 50 IU / kg once every seven days. In some embodiments, a subject is administered an initial dose of about 50 IU / kg, followed by either 50 IU / kg or 30 IU / kg every two to three days as needed.

[0124] In some embodiments, the methods disclosed herein are applied to determine personalized interval prophylaxis for a subject. As used herein, the term "personalized interval prophylaxis" refers to the use of efanesectocog alfa for personalized doses and / or dosing intervals or frequencies to prevent or inhibit the occurrence of one or more spontaneous and / or uncontrolled bleeding or bleeding episodes, or to reduce the frequency of one or more spontaneous and / or uncontrolled bleeding or bleeding episodes.

[0125] In some embodiments, a subject's treatment goal includes achieving a high FVIII plasma activity level and / or a high trough level. As used herein, a "trough level" in a hemophilia subject is a measurement of the lowest concentration reached by factor therapy, e.g., efanesectocog alfa therapy, before the next dose is administered. The methods disclosed herein can be used to determine a subject's dosing information to achieve a particular FVIII plasma activity level and / or trough level. Administration of efanesectocog alfa has been shown to successfully achieve high FVIII plasma activity levels and / or high trough levels in hemophilia A subjects.

[0126] In some embodiments, administration of efanesectocog alfa results in a FVIII activity level of 40% or greater in a subject for about 1, 2, 3, or 4 days. In some embodiments, administration of efanesectocog alfa results in higher FVIII activity in a subject for about 1, 2, 3, or 4 days. In some embodiments, administration of efanesectocog alfa results in a FVIII activity level of at least 40% in a subject for at least 3 days. In some embodiments, administration of efanesectocog alfa results in a FVIII activity level of at least 50% in a subject for about 4 days. In some embodiments, the efanesectocog alfa model [A] is used to determine dosing information for individual subjects to achieve a FVIII activity level of at least 40% in a subject for about 1, 2, 3, or 4 days.

[0127] Method, system and storage medium for estimating subject-specific dosing information, subject-individualized PK information and subject-median PK information Included herein is a method for estimating (e.g., calculating, determining, or providing) personalized efanesectocog alfa dosing information for an individual subject, the method comprising: (a) receiving subject information and / or desired treatment outcome information by an application program programmed to operate with an efanesectocog alfa popPK model (e.g., efanesectocog alfa popPK model [A]); (b) calculating personalized efanesectocog alfa dosing information using the efanesectocog alfa popPK model and the received information; and (c) outputting the calculated personalized efanesectocog alfa dosing information of (b). Also disclosed herein are methods further comprising: (c) selecting a dosing regimen based on the output personalized dosing information; and administering efanesectocog alfa to the subject according to the selected dosing regimen. One or more of the above steps may be performed using one or more of a software-based system, a network-based system, a computing system, or various combinations of the aforementioned systems. For example, an exemplary network-based system can be used to obtain estimated subject individualized dosing information, subject individualized PK information, and subject median PK information.

[0128] In some embodiments, (a) further includes receiving the target information by a software-based system.

[0129] In some embodiments, subject information includes age, self-reported race and / or weight. Additional subject information may further include diagnostic (baseline) FVIII level, PK determination, time of PK sampling, dosing history if PK samples were taken from multiple doses, actual dose, FVIII activity level, etc.

[0130] In some embodiments, the output information includes, for example, PK curves, PK parameters such as incremental recovery (Cmax / dose), mean residence time, terminal t1 / 2, clearance, Vss, AUC / dose, dose and associated trough, and interval and associated trough.

[0131] For example, to assess individualized subject PK, the system may recommend that the user input two to three optimized PK sampling time points, in which case the system output may include the PK curve and one or more selected PK parameters.

[0132] As a further example, to select an individualized dosing regimen using the output individual PK parameters discussed in the previous paragraph, (i) the dose selected for acute treatment can be based on user input of the desired rise in plasma FVIII activity level after the dose, (ii) the dose selected for prophylaxis can be based on user input of the desired dosing interval, or (iii) the interval selected for prophylaxis can be based on user input for the desired dose. In the second case, the system output can be, for example, a table of doses and associated troughs, such as x IU / kg, 10% trough, y IU / kg, 20% trough, etc. In the third case, the system output can be, for example, a table of intervals and associated troughs, such as x days, 10% trough, y IU / kg, 20% trough, etc.

[0133] In some embodiments, a user may wish to use the system without inputting individualized PK data. In some embodiments, the dosing output will be based on a population mean or median, rather than being individualized for a particular subject. In some embodiments, the user inputs, for example, body weight and / or self-reported race, as well as (i) a desired increase in plasma FVIII activity level after the dose, (ii) a desired dose interval for prophylaxis, or (iii) a desired dose for prophylaxis. In the first case, the system can output a dose. In the second case, the system can output a dose and an associated trough. In the third case, the system can output an interval and an associated trough.

[0134] The system may be compliant with patient privacy laws. In some embodiments, the system is encrypted, for example with SSL. In some embodiments, the information entered is made anonymous.

[0135] In some embodiments, the system includes a user help feature.

[0136] In some embodiments, the method may be performed by, for example, the subject, a doctor, a nurse, or another healthcare professional. In some embodiments, the method is performed by the subject.

[0137] Some embodiments include a computer-readable storage medium having stored thereon instructions that, when executed by a processor, cause the processor to perform one or more steps of the above-described methods.

[0138] Some embodiments include a system including a processor and a memory, the memory storing instructions that, when executed by the processor, cause the processor to perform any of the methods described above.

[0139] A user of the system or computer readable storage medium may be, for example, a subject or a caregiver or a doctor, nurse or other medical professional.

[0140] In some embodiments, the subject information input into the system includes body weight. In some embodiments, the subject information input into the system is self-reported race. In some embodiments, the desired therapeutic outcome information is a desired increase in plasma FVIII activity level after dosing, and the output information is a dose for acute treatment. In some embodiments, the desired therapeutic outcome information is a desired dosing interval, and the output information is a dose for prophylaxis. In some embodiments, the desired therapeutic outcome information is a desired dose, and the output information is an interval for prophylaxis.

[0141] In some embodiments, the individual efanesectocog alfa PK information includes 2-3 PK sampling time points. In some embodiments, the individual efanesectocog alfa PK information includes one or more of the subject's weight, diagnostic (baseline) factor level, dosing history if PK samples were taken from multiple doses, actual dose, actual time of PK sample collection, factor activity level, subject's weight, and / or subject's self-reported race.

[0142] In some embodiments, the output individualized subject PK comprises PK parameters selected from PK curves or ascending recovery (Cmax / dose), mean residence time, terminal t1 / 2, clearance, Vss, and AUC / dose. In some embodiments, the desired treatment outcome information based on the individual subject's PK is a desired increase in plasma FVIII activity level after dosing, and the output information is a dose for acute treatment.

[0143] In some embodiments, the methods disclosed herein include an electronic device. The electronic device can include, but is not limited to, a device having a processor and memory for executing and storing instructions. The electronic device can also include a display and one or more computer input devices, such as a keyboard, mouse, pad, touchscreen, microphone, and / or joystick. In some embodiments, the electronic device is a general-purpose computing device and data communication device, such as a digital pen, smartphone, smartwatch, tablet computer, personal digital assistant, handheld computer, laptop computer, point-of-sale transaction device, scanner, camera, and fax machine. The electronic device can also have multiple processors and multiple shared or separate memory components. For example, the electronic device can be a clustered computing environment or a server farm.

[0144] Alternatively, the electronic device may be a specialized data collection, computing, and communication device, such as a point-of-care (POC) device capable of receiving subject demographic information, including vital signs including age, weight, and / or blood characterizing values ​​including self-reported race. Blood characteristic values ​​may be received by the electronic device via a data communication channel, manual input, and / or a diagnostic process performed by the electronic device. Diagnostic processes performed on subject blood samples within the device may include ultrasound, impedance, conductivity, and / or optical measurements. The electronic device may be further configured to receive, detect, record, and / or transmit additional subject information, including diagnostic (baseline) FVIII levels, PK determinations, PK sampling times, dosing history if PK samples are taken from multiple doses, actual doses, and FVIII activity levels. The electronic device communicates with one or more network-based (e.g., web-based) application programs via one or more networks, such as the Internet. Similar to the electronic device, the network-based (e.g., web-based) application programs may be implemented using a general-purpose computer, a server, or other devices capable of providing data to the electronic device. The electronic device can receive personalized subject efanesectocog alfa PK information from a network-based (e.g., web-based) server and program. In some embodiments, the electronic device can assist in selecting a dosing regimen based on the output calculated subject PK information.

[0145] The methods and systems described herein may be implemented within or via a mobile device. Examples of mobile devices include navigation devices, mobile phones, smartphones, smartwatches, tablets, mobile personal digital assistants, laptops, palmtops, netbooks, pagers, e-readers, music players, etc. These devices may include, among other components, storage media such as flash memory, buffers, RAM, ROM, and one or more computing devices. The computing device associated with the mobile device may be adapted to execute program code, methods, and instructions stored thereon. As another example, the mobile device may be configured to execute instructions in cooperation with other devices. The mobile device may communicate with a base station connected to a server and configured to execute program code. The mobile device may also communicate via a peer-to-peer network, a mesh network, or other communication network. The program code may be stored in a storage medium associated with the server and executed by a computing device embedded in the server. The base station may include a computing device and a storage medium. The storage medium may store program code and instructions executed by a computing device associated with the base station. In some embodiments, the methods and systems described herein relate to a kit for collecting target information. While different embodiments of the kit may include different components, an exemplary kit includes a diagnostic device, such as a processing and / or computing element, for obtaining information from a subject, and a transmitting element that transmits the subject information to a computing device via a wired or wireless connection. The transmitting element in the kit may be configured to transmit the subject information in real time as the device is being used, or the diagnostic information may be transmitted upon receiving a command from a user or provider. Any of the components of the kit, such as the main body, may be configured as a hands-free unit during use or as a handheld unit during use.

[0146] Exemplary Computing Environment for the Disclosed Methods and Systems The various modeling techniques, dosage calculations, and estimations described herein can be implemented by software, firmware, hardware, or a combination thereof. Figure 1 shows an exemplary computer system 1900 in which embodiments, or portions thereof, can be implemented as computer-readable code. In another embodiment, the modeling disclosed in the Examples herein for efanesectocog alfa can be implemented in system 1900.

[0147] Computer system 1900 includes one or more processors, such as processor 1904. Processor 1904 is connected to a communication infrastructure 1906 (e.g., a bus or network).

[0148] Computer system 1900 also includes main memory 1908, preferably random access memory (RAM), and may also include secondary memory 1910. Depending on the implementation, user interface data may be stored in main memory 1908, for example, without limitation. Main memory 1908 may include, for example, cache and / or static RAM and / or dynamic RAM. Secondary memory 1910 may include, for example, a hard disk drive and / or a removable storage drive. Removable storage drive 1914 may include a floppy disk drive, magnetic tape drive, optical disk drive, flash memory, etc. Removable storage drive 1914 reads from and / or writes to removable storage unit 1916, in well-known fashion. Removable storage unit 1916 may include a floppy disk, magnetic tape, optical disk, etc. that is read from and written to by removable storage drive 1914. As will be appreciated by those skilled in the art, removable storage unit 1916 includes a computer-readable storage medium having stored thereon computer software and / or data.

[0149] Computer system 1900 may also include a display interface 1902. Display interface 1902 may be adapted to communicate with a display unit 1930. Display unit 1930 may include a computer monitor or similar means for displaying graphics, text, and other data received from main memory 1908 via communications infrastructure 1906. In alternative implementations, secondary memory 1910 may include other similar means for allowing computer programs or other instructions to be loaded into computer system 1900. Such means may include, for example, a removable storage unit 1922 and an interface 1920. Examples of such means may include a program cartridge and cartridge interface, a removable memory chip (e.g., EPROM or PROM) and associated socket, and other removable storage unit 1922 and interface 1920 that allow software and data to be transferred from the removable storage unit 1922 to computer system 1900.

[0150] Computer system 1900 may also include a communications interface 1924. Communications interface 1924 allows software and data to be transferred between computer system 1900 and external devices. Communications interface 1924 may include a modem, a network interface (such as an Ethernet card or WiFi), a communications port, a PCMCIA slot and card, or the like. The software and data transferred via communications interface 1924 are in the form of signals, which may be electronic, electromagnetic, optical, or other signals capable of being received by communications interface 1924. These signals are provided to communications interface 1924 via communications path 1926. Communications path 1926 carries signals and may be implemented using wire or cable, fiber optic, a phone line, a cellular phone link, WiFi, Bluetooth, an RF link, or other communications channel.

[0151] As used herein, the term "computer-readable storage medium" is used to generally refer to non-transitory storage media such as removable storage unit 1916, removable storage unit 1922, and a hard disk installed in hard disk drive 1912. The computer-readable storage medium may also refer to one or more memories such as main memory 1908 and secondary memory 1910, which may be memory semiconductors (e.g., DRAM, etc.). These computer program products are means for providing software to computer system 1900.

[0152] Computer programs (also called computer control logic) are stored in main memory 1908 and / or secondary memory 1910. Computer programs may also be received via communications interface 1924 and stored in main memory 1908 and / or secondary memory 1910. Such computer programs, when executed, enable computer system 1900 to implement embodiments described herein. In particular, computer programs, when executed, enable processor 1904 to implement processes of the present disclosure, such as the specific methods described above. Such computer programs thus represent controllers for computer system 1900. When an embodiment uses software, the software may be stored on a computer program product and loaded into computer system 1900 using removable storage drive 1914, interface 1920, or hard drive 1912.

[0153] Embodiments may be directed to computer program products including software stored on any computer-readable medium. Such software, when executed on one or more processing devices, causes the processing devices to operate as described herein. Embodiments may use any computer-usable or computer-readable medium. Examples of computer-readable storage media include, but are not limited to, non-transitory primary storage devices (e.g., any type of random access memory) and non-transitory secondary storage devices (e.g., hard drives, floppy disks, CD-ROMs, ZIP disks, tape, magnetic and optical storage devices, MEMS, nanotechnology storage devices, etc.). Other computer-readable media include communication media (e.g., wired and wireless communication networks, local area networks, wide area networks, intranets, etc.).

[0154] Non-limiting examples of software-based systems include network-based systems and web-based systems.

[0155] 3 illustrates an example computing device 400 and an example mobile computing device that can be used to implement the techniques described herein. Computing device 400 is intended to represent various forms of digital computers, such as laptops, desktops, workstations, personal digital assistants, servers, blade servers, mainframes, and other suitable computers. Mobile computing device is intended to represent various forms of mobile devices, such as personal digital assistants, mobile phones, smartphones, and other similar computing devices. The components, their connections and relationships, and their functions illustrated herein are intended to be exemplary only and are not intended to limit the implementation of the invention(s) described and / or claimed herein.

[0156] The computing device 400 includes a processor 402, a memory 404, a storage device 406, a high-speed interface 408 connecting to the memory 404 and multiple high-speed expansion ports 410, and a low-speed interface 412 connecting to a low-speed expansion port 414 and the storage device 406. Each of the processor 402, the memory 404, the storage device 406, the high-speed interface 408, the high-speed expansion port 410, and the low-speed interface 412 are interconnected using various buses and may be mounted on a common motherboard or in other suitable manner. The processor 402 processes instructions for execution within the computing device 400, including instructions stored in the memory 404 or the storage device 406, and can display graphical information for a GUI on an external input / output device, such as a display 416 coupled to the high-speed interface 408. Other implementations may use multiple processors and / or multiple buses, along with multiple memories and types of memory, as appropriate. Multiple computing devices may also be connected, each providing a portion of the required operations (e.g., as a server bank, a cluster of blade servers, or a multiprocessor system).

[0157] The memory 404 stores information within the computing device 400. In some implementations, the memory 404 is one or more volatile memory units. In some implementations, the memory 404 is one or more non-volatile memory units. The memory 404 may also be another form of computer-readable medium, such as a magnetic disk or optical disk.

[0158] The storage device 406 can provide mass storage for the computing device 400. In some implementations, the storage device 406 can be or include a computer-readable medium, such as a floppy disk device, a hard disk device, an optical disk device, or a tape device, a flash memory or other similar solid-state memory device, or an array of devices, including devices in a storage area network or other configuration. A computer program product can be tangibly embodied in an information carrier. The computer program product can also include instructions that, when executed, perform one or more methods, such as those described above. The computer program product can also be tangibly embodied in a computer-readable or machine-readable medium, such as memory 404, the storage device 406, or memory on the processor 402.

[0159] The high-speed interface 408 manages bandwidth-intensive operations of the computing device 400, while the low-speed interface 412 manages less bandwidth-intensive operations. Such functional allocation is merely exemplary. In some implementations, the high-speed interface 408 is coupled to the memory 404, the display 416 (e.g., through a graphics processor or accelerator), and a high-speed expansion port 410 that can accept various expansion cards (not shown). In this implementation, the low-speed interface 412 is coupled to the storage device 406 and the low-speed expansion port 414. The low-speed expansion port 414 may include various communication ports (e.g., USB, Bluetooth, Ethernet, wireless Ethernet), but may also be coupled to one or more input / output devices, such as a keyboard, a pointing device, a scanner, or a networking device such as a switch or router, for example, via a network adapter.

[0160] Computing device 400, as shown, can be implemented in several different forms. For example, it can be implemented as a standard server 420 or multiple times within a cluster of such servers. It can also be implemented in a personal computer, such as a laptop computer 422. It can also be implemented as part of a rack server system 424. Alternatively, components from computing device 400 can be combined with other components in a mobile device (not shown), such as mobile computing device 450. Each such device can include one or more of computing device 400 and mobile computing device 450, and the entire system can be made up of multiple computing devices communicating with each other.

[0161] Mobile computing device 450 includes, among other components, a processor 452, memory 464, input / output devices such as a display 454, a communication interface 466, and a transceiver 468. Mobile computing device 450 may also be provided with a storage device such as a microdrive or other device to provide additional storage. Each of processor 452, memory 464, display 454, communication interface 466, and transceiver 468 are interconnected using various buses, and some of the components may be mounted on a common motherboard or otherwise as appropriate.

[0162] The processor 452 can execute instructions, including instructions stored in the memory 464, within the mobile computing device 450. The processor 452 can be implemented as a chipset of chips including separate analog and digital processors. The processor 452 can provide for coordination of other components of the mobile computing device 450, such as control of a user interface, applications executed by the mobile computing device 450, wireless communication by the mobile computing device 450, etc.

[0163] The processor 452 can communicate with a user via a control interface 458 and a display interface 456 coupled to a display 454. The display 454 can be, for example, a TFT (thin film transistor liquid crystal display) display, an OLED (organic light emitting diode) display, or other suitable display technology. The display interface 456 can include appropriate circuitry for driving the display 454 to present graphical and other information to the user. The control interface 458 can receive commands from the user and translate them for submission to the processor 452. Additionally, an external interface 462 can provide communication with the processor 452 to enable short-range area communication between the mobile computing device 450 and other devices. The external interface 462 can provide, for example, for wired communication in some implementations or wireless communication in other implementations; multiple interfaces can also be used.

[0164] Memory 464 stores information within mobile computing device 450. Memory 464 may be implemented as one or more computer-readable media, one or more volatile memory units, or one or more nonvolatile memory units. Expansion memory 474 may be provided and connected to mobile computing device 450 via expansion interface 472, which may include, for example, a Single In-Line Memory Module (SIMM) card interface. Expansion memory 474 may provide additional storage space for mobile computing device 450 or store applications or other information for mobile computing device 450. Specifically, expansion memory 474 may include instructions for implementing or supplementing the processes described above and may also include secure information. Thus, for example, expansion memory 474 may be provided as a security module for mobile computing device 450 and may be programmed with instructions that enable secure use of mobile computing device 450. Additionally, secure applications may be provided via a SIMM card, along with additional information, such as placing identifying information on the SIMM card in an unhackable manner.

[0165] The memory may include, for example, flash memory and / or NVRAM memory (non-volatile random access memory), as described below. In some implementations, the computer program product is tangibly embodied on an information carrier. The computer program product includes instructions that, when executed, perform one or more methods, such as those described above. The computer program product may be a computer-readable or machine-readable medium, such as memory 464, expansion memory 474, or memory on processor 452. In some implementations, the computer program product may be received in a propagated signal, for example, via transceiver 468 or external interface 462.

[0166] Mobile computing device 450 can communicate wirelessly via communication interface 466, which may optionally include digital signal processing circuitry. Communication interface 466 can provide communications under various modes or protocols, such as GSM (Global System for Mobile Communications) voice calls, SMS (Short Message Service), EMS (Enhanced Message Service) or MMS (Multimedia Messaging Service), CDMA (Code Division Multiple Access), TDMA (Time Division Multiple Access), PDC (Personal Digital Cellular), WCDMA (Wideband Code Division Multiple Access), CDMA2000, or GPRS (General Packet Radio Service). Such communications can occur, for example, via transceiver 468 using radio frequencies. Additionally, short-range communications can occur, such as using Bluetooth, WiFi, or other such transceivers (not shown). Additionally, a GPS (Global Positioning System) receiver module 470 can provide additional navigation- and location-related wireless data to mobile computing device 450, which can be used as appropriate by applications executing on mobile computing device 450.

[0167] Mobile computing device 450 can also communicate voice using audio codec 460, which can receive voice information from a user and convert it into usable digital information. Audio codec 460 can also generate audible sounds for the user, for example, through a speaker in the handset of mobile computing device 450. Such sounds can include sounds from a voice call, recorded sounds (e.g., voice messages, music files, etc.), and sounds generated by applications running on mobile computing device 450.

[0168] The mobile computing device 450, as shown, can be implemented in several different forms, for example, as a mobile phone 480. It can also be implemented as part of a smartphone 482, personal digital assistant, or other similar mobile device.

[0169] Various implementations of the systems and techniques described herein may be realized in digital electronic circuitry, integrated circuits, specially designed ASICs (application-specific integrated circuits), computer hardware, firmware, software, and / or combinations thereof. These various implementations may include implementation in one or more computer programs executable and / or interpretable by a programmable system including at least one programmable processor, which may be special purpose or general purpose, coupled to receive data and instructions from, and transmit data and instructions to, a storage system, at least one input device, and at least one output device.

[0170] These computer programs (also referred to as programs, software, software applications, or code) include machine instructions for a programmable processor and may be implemented in a high-level procedural and / or object-oriented programming language and / or assembly / machine language. As used herein, the terms machine-readable medium and computer-readable medium refer to any computer program product, apparatus, and / or device (e.g., magnetic disk, optical disk, memory, programmable logic device (PLD)) used to provide machine instructions and / or data to a programmable processor, including a machine-readable medium that receives machine instructions as a machine-readable signal. The term machine-readable signal refers to any signal used to provide machine instructions and / or data to a programmable processor.

[0171] To provide for user interaction, the systems and techniques described herein can be implemented on a computer having a display device (e.g., a CRT (cathode ray tube) or LCD (liquid crystal display) monitor) for displaying information to the user, and a keyboard and pointing device (e.g., a mouse or trackball) by which the user can provide input to the computer. Other types of devices can be used to provide for user interaction as well; for example, feedback provided to the user can be any form of sensory feedback (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user can be received in any form, including acoustic, speech, or tactile input.

[0172] The systems and techniques described herein may be implemented in a computing system that includes back-end components (e.g., as data servers), middleware components (e.g., application servers), or front-end components (e.g., client computers having a graphical user interface or web browser that allows a user to interact with an implementation of the systems and techniques described herein), or any combination of such back-end, middleware, or front-end components. The components of the system may be interconnected by any form or medium of digital data communication (e.g., a communication network). Examples of communication networks include a local area network (LAN), a wide area network (WAN), and the Internet.

[0173] A computing system may include clients and servers. Clients and servers are generally remote from each other and typically interact through a communication network. The relationship of client and server arises by virtue of computer programs running on the respective computers and having a client-server relationship to each other.

[0174] Having now described the present disclosure in detail, it will be more clearly understood by reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the disclosure. All patents and publications mentioned herein are expressly incorporated by reference. [Example]

[0175] Example 1. Population Pharmacokinetic (PopPK) Model to Characterize Evanesoctocog Alpha Factor VIII (FVIII) Activity Levels in Patients with Severe Hemophilia A Once-weekly efanesectocog alfa provided high, sustained FVIII activity in the normal to near-normal range for most weeks and demonstrated superior bleeding protection compared with previous FVIII prophylaxis. FVIII activity data were collected from five clinical studies (Phase 1 / 2a single- and multiple-dose studies in adults [NCT03205163 and EudraCT 2018-001535-51, respectively]; Phase 3 studies in adults and adolescents aged 12 years and older [XTEND-1, NCT04161495] and children aged 1 year to less than 12 years [XTEND-Kids, NCT04759131]; and a Phase 3 long-term extension study [XTEND-ed, NCT04644575]). A popPK model was developed to characterize FVIII activity after efanesectocog alfa administration, identify intrinsic and extrinsic factors affecting pharmacokinetics (PK), and assess PK variability.

[0176] FVIII activity levels used to develop the popPK model were measured by a one-stage coagulation assay from 3,054 blood samples from 199 adults and adolescents and 61 children who received efanesectocog alfa in the study described above. Body weight and VWF levels ranged from 12.5 kg to 133 kg and 40 IU / dL to 339 IU / dL, respectively. A one-compartment model with linear elimination was used to characterize FVIII activity using estimated allometric body weight effects on clearance (CL) and central compartment volume (V), accounting for the dependence of CL and V on body size. The efanesectocog alfa popPK model is shown above as equation [A].

[0177] Baseline VWF, baseline race, ethnicity (Caucasian and Asian), baseline hematocrit, hepatitis C virus and human immunodeficiency virus status, and blood type (A, B, O) were tested for statistical significance in covariate analyses. Baseline descriptive statistics of continuous covariates for subjects in the final dataset are shown in Table 1. The final popPK model was used to simulate various dose regimens in a hypothetical population of adult and adolescent patients generated using baseline weight distributions from the Phase 1 / 2 study and XTEND-1.

[0178] [Table 1]

[0179] result: Table 2 shows the C at week 26 of efanesectocog alfa prophylaxis for adult and adolescent populations from the Phase 3 clinical trial. maxss and C trough Parameters and C at 26th week maxss and C trough PopPK model estimates (observational or non-compartmental analysis) are shown. As shown from the comparison in Table 2, the PK parameter estimates from the PopPK model are consistent with the clinical trial data.

[0180] [Table 2]

[0181] [Table 3]

[0182] The final popPK model described FVIII activity over time, captured interindividual variability in FVIII activity, and accurately estimated moderate interindividual variability in CL and V (Table 3). The allometric index of the body weight effect indicated that CL and V increased with body weight, with lower body weight resulting in overall more rapid elimination. Asian race was identified as a statistically significant covariate for CL (P<0.001). CL was 10.4% lower in Asians than in non-Asians. Baseline VWF levels were not identified as a statistically significant covariate in the final popPK model, consistent with previous studies demonstrating that the PK of efanesectocog alfa is VWF-independent. For example, Figure 4 shows the independence of efanesectocog alfa clearance on baseline VWF levels in adult and adolescent patients. Blood type was not identified as a statistically significant covariate in the final popPK model. The simulated steady-state FVIII activity over time for efanesectocog alfa and population and individual predicted versus observed FVIIII activity in the final PopPK model is shown in Figure 5 , which illustrates FVIII activity >40 IU / dL for 3-4 days post-dose.

[0183] The final popPK model demonstrated that a once-weekly efanesoctocog alfa (50 IU / kg) prophylaxis regimen resulted in a steady-state C of >10 IU / dL in the majority of adult and adolescent patients, regardless of weight or race. troughdemonstrated that the time to 40 IU / dL FVIII activity was 3 to 4 days. Simulations for perioperative management during major surgery and treatment of major bleeding showed that a loading dose of 50 IU / kg, followed by a loading dose of 30 IU / kg every 2 to 3 days in the postoperative period, met the World Federation of Hemophilia guidelines for peak FVIII activity for most adults and adolescents. Similarly, for minor surgery and treatment of mild to moderate bleeding, a single dose of 50 IU / kg of efanesectocog alfa resulted in peak FVIII activity (>50 IU / dL to 80 IU / dL) that met these guidelines.

[0184] Conclusions: A linear one-compartment popPK model was able to adequately characterize FVIII activity in patients with severe hemophilia A. CL and V were dependent on body weight, and Asian race was identified as a covariate for CL; however, the limited effects of body weight and Asian race on FVIII exposure were not considered clinically meaningful. PopPK simulations demonstrated that in most adults and adolescents, efanesectocog alfa at 50 IU / kg once weekly achieved sustained FVIII activity in the normal to near-normal range (>40 IU / dL) for 3 to 4 days, with activity levels exceeding 10 IU / dL on day 7. PopPK simulations also supported the phase 3 dosing regimens selected for routine prophylaxis, treatment of bleeding episodes, and perioperative management. Individual clearance of efanesectocog alfa was independent of baseline VWF in adults and adolescents.

[0185] Further details on the development of the popPK model Available data from adult, adolescent, and pediatric phase 3 studies with efanesoctocog alfa were incorporated into the development of a population pharmacokinetic (PopPK) model. Complete data from adult and adolescent studies and partial data from pediatric and long-term safety studies were included.

[0186] [Table 4]

[0187] Definitions in Table 4: a) Number of exposures to efanesectocog alfa in each study for PopPK model development; total N=260, including 199 adult and adolescent patients and 61 pediatric patients in EFC15295; b) Only patients who underwent surgery in the LTS16294 study (3 patients) were included in PopPK model development; c) In EFC16293, 17 patients were in the sequential arm, and patients skipped doses on day 7 of week 1 and day 7 of week 26 to allow estimation of end-phase half-life by collection of single-stage coagulation (OSC) FVIII activity samples up to day 15 after the dose on day 1 and week 26.

[0188] In the phase 1 PopPK analysis, the OSC FVIII activity data were described using the 1-CMT model with body weight as a covariate for CL, V, and hematocrit level as a covariate for V. In the final PopPK analysis, the 1-CMT model was selected as the structural model to describe the OSC FVIII activity profile, and the base model included the WT effect. Further covariate screening was performed with the base PopPK model.

[0189] Body weight (kg) (WT) or other continuous covariates were scaled to the median baseline WT (median baseline value) in adults and adolescents (78.3 kg) to assess covariate effects in adults or contrast growth effects in children.

[0190] For example, for adult covariate effects and child contrast growth effects, CL = TVCL × (WT 時間-変動 / 78.3) CLexp × (exp(ETA1)). A similar approach was used for volume.

[0191] Dataset: One popPK dataset for observed data is based on the adult / adolescent study EFC16293. Figures 6A and 6B show baseline-corrected FVIII activity time profiles. Day 1 (baseline) is shown for all patients (Figure 6A). Day 1 (baseline) and week 26 are shown for sequential arm patients (Figure 6B). FVIII activity time profiles follow typical one-compartment (linear decline on a logarithmic scale) kinetics. FVIII activity shows a mean half-life of efanesectocog alfa of 47.8 hours.

[0192] The correlations between the four continuous covariates at baseline are shown in Figure 7. The median baseline weight (WTKGB) was 78.3, excluding the EFC16295 study. Baseline race (BH) had a median of 43 (also excluding the EFC16295 study). Baseline VWF (BVWF) showed a median of 112 (also excluding the EFC16295 study). Age was not tested as a covariate because it was thought to be correlated with WT. Race and VWF were tested as covariates and found to be non-significant.

[0193] The distribution of categorical covariates, such as blood type, race, HIV status, and HCV status, is shown in Table 5. The data in Table 5 include all studies (n=260). Black (1.92%) and other races (3.08%) were present in approximately 5% of patients. Regarding blood type, blood types A and O were prevalent, accounting for 29.62% and 36.15%, respectively. Blood type B was present in less than 10% (9.23%) of patients. Blood type AB was present in less than 5% (3.85%) of patients. HCV- and HIV-positive patients were elderly, and pediatric patients were not HCV- or HIV-positive. There were two patients under the age of 2 years. Of the categorical factors shown, only HCV status, HIV status, blood type (A, B, and O), and race (White and Asian) were tested as covariates.

[0194] [Table 5]

[0195] OSC activity is the concentration (C) in the central compartment. All parameters in the base and final covariate models were estimated with acceptable accuracy. Adding body weight effects reduced the instrumental variable estimates (IIV) for CL and V, whereas adding Asian race effects on CL reduced the IIV for CL. The WT effect indices for CL and V are acceptable when compared with simple allometric indices. The influence of Asian race was confirmed for CL, with clearance in Asians being 10.4% lower than that of non-Asians of the same weight.

[0196] Figures 8A and 8B show the population prediction (PRED) and individual prediction (IPRED) for DV, respectively, demonstrating that the population and individual models can describe the PK data across age categories.

[0197] Figure 9 shows the visual predictive check (VPC) of the final PopPK model. The VPC for each study indicates that the majority of observed FVIII activity data fell within the predicted range [5th to 95th percentile]. For the purposes of VPC, one unique patient from LTS16294 was considered in EFC16293.

[0198] Figures 10A and 10B show the population prediction (PRED) and individual prediction (IPRED) vs. DV for surgery, respectively. Data from 19 patients, EFC16293, EFC16295, and LTS16294, during the surgery timeframe are included. The model performs reasonably well in describing the PK data collected during surgery and after ad hoc surgical dosing.

[0199] Figure 11 shows the steady-state C across the entire population by baseline weight (kg). trough , C maxss Figure 12 shows the distribution of time to steady-state C and 40 IU / dL FVIII activity across non-Asian and Asian populations for all age groups. trough , C maxss The distribution of time to 40 IU / dL is shown.max , C trough The time to FVIII activity and 40 IU / dL increase with increasing body weight and are higher in Asians compared with non-Asians. However, regardless of body weight and race, the 50 IU / kg QW prophylaxis regimen significantly reduces the steady-state C > 10 IU / dL. trough demonstrated that a time to 40 IU / dL FVIII activity of 3-4 days was achieved in the majority of adult and adolescent (age ≥ 12 years) populations. A 50 IU / kg QW prophylaxis regimen was associated with a 2-3 day steady-state C trough It was also shown that time to >5 IU / dL and 40 IU / dL FVIII activity was achieved in the majority of the pediatric (age <12 years) population.

[0200] Major surgery and major bleeding: The model was analyzed for major surgery and major bleeding. Major surgery and major bleeding were classified based on the criteria listed in Table 6.

[0201] [Table 6]

[0202] For major surgery and hemorrhage, the simulations were based on a single-dose dosing regimen at 50 IU / kg with booster doses of 30 or 50 IU / kg every 2-3 days as needed. Thus, 50 IU / kg Q2D, 50 IU / kg Q3D, 30 IU / kg Q2D, and 30 IU / kg Q3D are possible combinations of dosing regimens after a preoperative dose of 50 IU / kg (QXD is every X days). These same simulations can be applied to both major surgery and major hemorrhage, as both involve the same dosing combinations.

[0203] 13 shows simulated OSC FVIII activity for major bleeding and major surgery over time in subjects under the age of 6. Over the entire surgical period, more than 95% of patients aged 6 years and older met the major surgery criteria, and more than 80% of patients under the age of 6 met the surgery criteria.

[0204] Figure 14 shows simulated FVIII activity in a simulated adult and adolescent population with efanesectocog alfa at a dose of 50 IU / kg, followed by 30 IU / kg every 3 days until day 14. The simulation showed that an initial dose of 50 IU / kg, followed by 30 IU / kg every 3 days until day 14, should be sufficient for perioperative management during major surgery (Figure 15) as well as treatment of major bleeding. More than 95% of adult and adolescent patients were predicted to meet the World Federation of Hemophilia (WFH) guidelines (Srivastava A, et al. Haemophilia. 2020;26 Suppl 6:1-158) for peak FVIII activity (>80-100 IU / dL preoperatively or on the day of major bleeding). Additionally, other dosing regimens were simulated, such as an initial dose of 50 IU / kg followed by 50 or 30 IU / kg every 2 or 3 days, and these additional dosing regimens were predicted to also meet the WFH Peak FVIII guidelines. Thus, the simulations showed that an initial dose of 50 IU / kg followed by 50 or 30 IU / kg every 2 or 3 days meets the WFH Peak FVIII guidelines in the majority (>95%) of adult and adolescent patients managed during major surgery and treatment of major bleeding.

[0205] Minor surgery and mild or moderate bleeding: Figure 15 shows simulated OSC FVIII activity over time for all age groups. Over 95% of patients in all age groups meet the criterion of peak FVIII > 50 IU / dL after preoperative dosing for minor surgery. Similarly, over 95% of patients in all age groups meet the criterion of peak FVIII > 40 IU / dL required for mild / moderate bleeding management. With an additional dose of 30 or 50 IU / kg every 2 or 3 days, over 95% of patients in all age groups meet the criterion of peak FVIII > 50 IU / dL.

[0206] Conclusions: Based on this data, the one-compartment (1-CMT) model reasonably well describes adult, adolescent, and pediatric OSC FVIII activity data. Body weight effects (on CL and V) were included in the base model, and Asian race effects (on CL) were identified as statistically significant covariates. Simulations for various body weights indicate that a fixed regimen of 50 IU / kg QW provides high FVIII activity in adult, adolescent, and pediatric populations, regardless of weight and race. Simulations using this model also support and suggest potential efanesectocog alfa dosing schemes for surgical and bleeding scenarios.

[0207] Embodiments of the present disclosure The present disclosure includes, but is not limited to, the following exemplary embodiments.

[0208] Embodiment 1. A method of determining efanesectocog alfa dosing information for an individual subject, comprising: receiving subject-specific information and calculating efanesectocog alfa dosing information using a software-based system; The system was programmed to implement a one-compartment efanesoctocog alfa popPK model. The efanesectocog alfa popPK model includes body weight as a covariate, and the efanesectocog alfa popPK model does not include VWF levels or hematocrit levels as covariates.

[0209] Embodiment 2. The method of embodiment 1, further comprising outputting, by a software-based system, medication information regarding the subject.

[0210] Embodiment 3. The method of embodiment 2, further comprising outputting, by a software-based system, a suggested dosing regimen.

[0211] Embodiment 4. The method of any one of embodiments 1 to 3, wherein desired treatment outcome information is also received.

[0212] Embodiment 5. A method of estimating personalized efanesectocog alfa dosing information for a subject, comprising: (a) receiving, by a processing device, subject information and / or desired treatment outcome information by an application program programmed to operate with the efanesectocog alfa popPK model, wherein the received information is transmitted by one or more electronic devices; (b) using at least a software-based system to calculate individualized efanesectocog alfa dosing information using the efanesectocog alfa popPK model and the received information; and (c) transmitting the calculated personalized efanesectocog alfa dosing information of (b) to one or more electronic devices to output the information; wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0213] Embodiment 6. A method of estimating personalized efanesectocog alfa dosing information for a subject, comprising: (a) receiving, by one or more electronic devices, subject information and / or desired treatment outcome information; (b) transmitting, by the processing device, the subject information and / or desired treatment outcome information to an application program, the application being programmed to implement the efanesectocog alfa popPK model; (c) receiving from the application program personalized efanesectocog alfa dosing information calculated using the efanesectocog alfa popPK model and the information transmitted in (b); and (d) outputting the personalized efanesectocog alfa dosing information by one or more electronic devices; wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0214] Embodiment 7. A method of providing an efanesoctocog alfa dosing regimen based on median popPK, comprising: (a) receiving, via a software-based system, subject information and / or desired treatment outcome information including an efanesectocog alfa popPK model; (b) calculating, by a software-based system, median PK information using the efanesoctocog alfa popPK model and the received information; (c) A software-based system will output median PK information. wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0215] Embodiment 8. A method of providing an efanesectocog alfa dosing regimen based on efanesectocog alfa median popPK, comprising: (a) receiving, by one or more electronic devices, subject information and / or desired treatment outcome information; (b) transmitting, by the processing device, the subject information and / or desired treatment outcome information to an application program, the application being programmed to implement the efanesectocog alfa popPK model; (c) receiving, from the application program, calculated efanesectocog alfa median PK dosing information using the efanesectocog alfa popPK model and received information; (d) outputting the median PK information by one or more electronic devices; wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0216] Embodiment 9. A method of providing an efanesoctocog alfa dosing regimen, comprising: (a) receiving, by a processing device, subject information and / or desired treatment outcome information by an application program programmed to implement an efanesectocog alfa population pharmacokinetic (popPK) model, wherein the received information is transmitted by one or more electronic devices; (b) calculating, by the application program, individualized efanesectocog alfa dosing information using the efanesectocog alfa popPK model and the received information; and (c) transmitting, by the processing device, the calculated dosing information of the individualized efanesectocog alfa dosing regimen of (b) to one or more electronic devices for outputting the information; wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0217] Embodiment 10. A method for estimating personalized target efanesectocog alfa PK information, comprising: (a) receiving, by a software-based system, subject information including an effanesoctocog alpha popPK model; (b) estimating, by a software-based system, individualized target efanesectocog alfa PK information using the efanesectocog alfa popPK model and the received information; and (c) A software-based system will output individualized phenesoctocog alfa PK information. wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0218] Embodiment 11. A method for estimating personalized target efanesectocog alfa PK information, comprising: (a) receiving, by one or more electronic devices, targeted information; (b) transmitting, by the processing device, the subject information to an application program, the application being programmed to implement the Fanesectocog alpha popPK model, the application program using the Fanesectocog alpha popPK model and the transmitted information to generate and transmit personalized subject Fanesectocog alpha PK information; (c) receiving personalized phenesoctocog alfa PK information from the application program; and (d) outputting the individualized PK information by one or more electronic devices; wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0219] Embodiment 12. A method for estimating personalized target efanesectocog alfa PK information, comprising: (a) receiving, by an application program programmed to implement the phenesoctocog alpha popPK model, subject information, the received information being transmitted by one or more electronic devices; (b) calculating, by the application program, personalized target efanesectocog alfa PK information for efanesectocog alfa using the efanesectocog alfa popPK model and the received information; (c) transmitting, by the processing device, the calculated individualized phenesoctocog alfa PK information of (b) to one or more electronic devices for outputting the information; wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0220] Embodiment 13. A method for estimating personalized target efanesectocog alfa PK information, comprising: (a) receiving, by one or more electronic devices, information regarding the individual's body weight and (i) a desired increase in plasma factor activity level after a dose, or (ii) a desired dose or a desired dose interval; (b) transmitting, by the processing device, the information of (a) to an application program, the application being programmed to implement the effanesoctocog alpha popPK model; and (c) receiving, from the web-based server and program, personalized phenesoctocog alfa PK information calculated using the phenesoctocog alfa popPK model and the transmitted information of (b); and (d) outputting, by one or more electronic devices, the calculated individualized target phenesoctocog alfa PK information; wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0221] Embodiment 14. The method of any one of embodiments 5 to 13, wherein the subject information includes the subject's weight.

[0222] Embodiment 15. The method of any one of embodiments 5 to 14, wherein the subject information includes a baseline FVIII activity level for the subject.

[0223] Embodiment 16. The method of any one of embodiments 5 to 15, wherein the subject information includes the subject's self-reported race.

[0224] Embodiment 17. The method of any one of embodiments 5 to 16, wherein the subject information includes whether the subject self-identifies as Asian.

[0225] Embodiment 18. The method of any one of embodiments 5 to 17, wherein the subject provides the subject information.

[0226] Embodiment 19. The method of any one of embodiments 5 to 17, wherein a medical professional provides the subject information.

[0227] Embodiment 20. The method of any one of embodiments 5 to 19, wherein the subject information does not include the subject's VWF or hematocrit levels.

[0228] Embodiment 21. The method of any one of embodiments 1 to 20, wherein the system is programmed to implement a one-compartment efanesectocog alfa popPK model that includes body weight as a covariate for calculating dosing information, and wherein the efanesectocog alfa popPK model does not include VWF or hematocrit levels as covariates.

[0229] Embodiment 22. The method of any one of embodiments 1-6, 8-9, or 14-21, further comprising selecting a dosing regimen based on the dosing information.

[0230] Embodiment 23. The method of any one of embodiments 7-8 or 10-21, further comprising selecting a dosing regimen based on PK information.

[0231] Embodiment 24. The method of embodiment 22 or 23, further comprising administering efanesoctocog alfa to the subject according to a selected dosing regimen.

[0232] Embodiment 25. The method of any one of embodiments 1-6, 8-9, 14-22, or 24, wherein the dosing information comprises estimated or predicted FVIII activity levels over time after administration of efanesectocog alfa.

[0233] Embodiment 26. The method of any one of embodiments 7-9 or 14-25, wherein the dosing regimen is a prophylactic regimen.

[0234] Embodiment 27. The method of any one of embodiments 7-9 or 14-25, wherein the dosing regimen is an on-demand regimen.

[0235] Embodiment 28. The method of any one of embodiments 7-9 or 14-25, wherein the dosing regimen is for perioperative management of bleeding.

[0236] Embodiment 29. The method of any one of embodiments 4 to 5, wherein the desired treatment outcome information comprises a desired FVIII activity level.

[0237] Embodiment 30. The method of embodiment 29, wherein the desired FVIII activity level comprises a minimum FVIII activity level between doses.

[0238] Embodiment 31 The method of embodiment 29, wherein the desired FVIII activity level comprises a minimum FVIII activity level at a certain point in time.

[0239] Embodiment 32. The method of embodiment 31, wherein this time point is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days after administration of efanesoctocog alfa.

[0240] Embodiment 33. The method of any one of embodiments 1 to 32, wherein the efanesoctocog alfa popPK model includes self-reported race as a covariate.

[0241] Embodiment 34. The method of any one of embodiments 1 to 32, wherein the effanesectocog alpha popPK model includes, as a covariate, whether the subject self-reports as Asian.

[0242] Embodiment 35. The method of embodiment 33 or 34, wherein the subject does not self-report as Asian.

[0243] Embodiment 36. The method of embodiment 33 or 34, wherein the subject self-reports to be Asian.

[0244] Embodiment 37. The method of any one of embodiments 1 to 38, wherein the efanesectocog alfa popPK model is efanesectocog alfa popPK model [A].

[0245] Embodiment 38. A method of treating hemophilia A in a subject in need thereof, comprising administering to the subject a dosage regimen selected according to any one of embodiments 1 to 37.

[0246] Embodiment 39. A device or system comprising a processor configured to provide dosing or PK information according to the method of any one of embodiments 1 to 38.

[0247] Embodiment 40.1 A data processing apparatus, device or system comprising a processor configured to implement a compartmental efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF levels or hematocrit levels as covariates.

[0248] Embodiment 41. A data processing apparatus, device or system as described in embodiment 40, wherein the effanesectocog alpha popPK model includes self-reported race as a covariate.

[0249] Embodiment 42. A data processing apparatus, device or system as described in embodiment 40, wherein the effanesectocog alpha popPK model includes as a covariate whether the subject self-reports as Asian.

[0250] Embodiment 43. The data processing device, device, or system of any one of embodiments 40 to 42, including a smartphone, tablet computer, personal digital assistant, handheld computer, laptop computer, or smartwatch.

[0251] Embodiment 44. A data processing device, device, or system according to any one of embodiments 40 to 42, including a smartphone.

[0252] Embodiment 45. A data processing device, device or system according to any one of embodiments 40 to 42, including a smartwatch.

[0253] Embodiment 46. A data processing apparatus, device or system according to any one of embodiments 40 to 45, wherein the processor is configured to implement the effanesoktocog alpha popPK model [A].

[0254] Embodiment 47. A computer program comprising instructions that, when the program is executed by a computer, cause the computer to perform the method according to any one of embodiments 1 to 38.

[0255] Embodiment 48. A computer program comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

[0256] Embodiment 49. The computer program of embodiment 48, wherein the effanesectocog alfa popPK model includes self-reported race as a covariate.

[0257] Embodiment 50. The computer program of embodiment 48, wherein the effanesectocog alpha popPK model includes, as a covariate, whether the subject self-reports as Asian.

[0258] Embodiment 51. The computer program of embodiment 48, wherein the efanesectocog alfa popPK model is efanesectocog alfa popPK model [A].

[0259] Embodiment 52. A computer-readable medium comprising instructions that, when executed by a computer, cause the computer to provide the method of any one of embodiments 1 to 38.

[0260] Embodiment 53. A computer-readable medium comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF levels or hematocrit levels as covariates.

[0261] Embodiment 54. The computer-readable medium of embodiment 53, wherein the effanesectocog alfa popPK model includes self-reported race as a covariate.

[0262] Embodiment 55. The computer-readable medium of embodiment 53, wherein the effanesectocog alpha popPK model includes, as a covariate, whether the subject self-reports as Asian.

[0263] Embodiment 56. The computer-readable medium of embodiment 53, wherein the efanesectocog alfa popPK model is efanesectocog alfa popPK model [A].

[0264] Embodiment 57. The method of embodiment 37, wherein the typical clearance estimate (TVCL) in the efanesoctocog alfa popPK model [A] is 0.433 dL / h.

[0265] Embodiment 58. The method of embodiment 37 or 57, wherein the typical volume estimate (TVV) in the efanesoctocog alfa popPK model [A] is 30.2 dL.

[0266] Embodiment 59. The method of any one of embodiments 37, 57 or 58, wherein the variability (η1) of clearance from the central compartment in the efanesoctocog alfa popPK model [A] is 0.0354.

[0267] Embodiment 60. The method of any one of embodiments 37 or 57-59, wherein the variation in the volume of the central compartment (η2) in the efanesoctocog alfa popPK model [A] is 0.0209.

[0268] Embodiment 61. A data processing apparatus, device or system as described in embodiment 46, wherein the typical clearance estimate (TVCL) in the efanesoctocog alfa popPK model [A] is 0.433 dL / h.

[0269] Embodiment 62. A data processing apparatus, device or system according to any one of embodiments 46 or 61, wherein the typical volume estimate (TVV) in the efanesoctocog alfa popPK model [A] is 30.2 dL.

[0270] Embodiment 63. A data processing apparatus, device or system according to any one of embodiments 46, 61 or 62, wherein the variability (η1) of clearance from the central compartment in the efanesoctocog alfa popPK model [A] is 0.0354.

[0271] Embodiment 64. A data processing apparatus, device or system according to any one of embodiments 46 or 61 to 63, wherein the variation in the volume of the central compartment (η2) in the efanesoctocog alpha popPK model [A] is 0.0209.

[0272] Embodiment 65. The computer program of embodiment 51, wherein the typical clearance estimate (TVCL) in the efanesoctocog alfa popPK model [A] is 0.433 dL / h.

[0273] Embodiment 66. A computer program according to embodiment 51 or 65, wherein the typical volume estimate (TVV) in the efanesoctocog alfa popPK model [A] is 30.2 dL.

[0274] Embodiment 67. The computer program of any one of embodiments 51, 65 or 66, wherein the variability in clearance from the central compartment (η1) in the efanesoctocog alfa popPK model [A] is 0.0354.

[0275] Embodiment 68. A computer program according to any one of embodiments 51 or 65 to 67, wherein the variability of the central compartment volume (η2) in the efanesoctocog alfa popPK model [A] is 0.0209.

[0276] Embodiment 69. The computer-readable medium of any one of embodiments 56, wherein the typical clearance estimate (TVCL) in the efanesoctocog alfa popPK model [A] is 0.433 dL / h.

[0277] Embodiment 70. The computer-readable medium of any one of embodiments 56 or 69, wherein the typical volume estimate (TVV) in the efanesoctocog alfa popPK model [A] is 30.2 dL.

[0278] Embodiment 71. The computer-readable medium of any one of embodiments 56, 69, or 70, wherein the variability in clearance from the central compartment (η1) in the efanesoctocog alfa popPK model [A] is 0.0354.

[0279] Embodiment 72. The computer-readable medium of any one of embodiments 56 or 69 to 71, wherein the variability of the central compartment volume (η2) in the efanesoctocog alfa popPK model [A] is 0.0209.

[0280] [Table 7]

[0281] [Table 8]

[0282] [Table 9]

[0283] [Table 10]

[0284] [Table 11]

[0285] [Table 12]

Claims

1. 1. A method for determining efanesectocog alfa dosing information for an individual subject, comprising: receiving the subject-specific information and calculating the efanesectocog alfa dosing information using a software-based system; The system is programmed to implement a one-compartment efanesoctocog alfa popPK model; A method wherein the efanesectocog alfa popPK model includes body weight as a covariate and wherein the efanesectocog alfa popPK model does not include VWF levels or hematocrit levels as covariates.

2. The method of claim 1 , further comprising outputting, by the software-based system, the medication information for the subject.

3. 3. The method of claim 2, further comprising outputting, by the software-based system, a suggested dosing regimen.

4. 1. A method for estimating personalized target efanesectocog alfa PK information, comprising: (a) receiving, by a software-based system, subject information including an effanesoctocog alpha popPK model; (b) estimating, by the software-based system, personalized target phenesoctocog alfa PK information using the phenesoctocog alfa popPK model and the received information; and (c) outputting, by the software-based system, the personalized phenesoctocog alfa PK information. wherein the efanesectocog alfa popPK model includes body weight as a covariate and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

5. 5. The method of claim 4, wherein the subject information comprises a baseline FVIII activity level for the subject.

6. The method of claim 4 , wherein a subject provides the subject information.

7. 7. The method of any one of claims 1 to 6, wherein the system is programmed to implement a one-compartment efanesectocog alfa popPK model that includes body weight as a covariate for calculating the dosing information, and the efanesectocog alfa popPK model does not include VWF or hematocrit levels as covariates.

8. 5. The method of claim 4, further comprising selecting a dosing regimen based on the PK information.

9. 9. The method of claim 8, further comprising administering efanesectocog alfa to the subject according to the selected dosing regimen.

10. The method of any one of claims 1 to 3, wherein the dosing information comprises estimated or predicted FVIII activity levels over time following administration of efanesectocog alfa.

11. The method of any one of claims 8 to 10, wherein the dosing regimen is a prophylactic regimen, an on-demand regimen, or for perioperative management of bleeding.

12. 12. The method of any one of claims 1 to 11, wherein the efanesectocog alpha popPK model includes as a covariate whether the subject self-reports as Asian.

13. The method of any one of claims 1 to 12, wherein the efanesectocog alfa popPK model is efanesectocog alfa popPK model [A].

14. The typical clearance estimate (TVCL) in the efanesectocog alfa pop-PK model [A] was 0.433 dL / h, the typical volume estimate (TVV) in the efanesectocog alfa pop-PK model [A] was 30.2 dL, and the variability of clearance from the central compartment (η １ ) was 0.0354, and the variation in the central compartment volume (η ２ 14. The method of claim 13, wherein ≈0.0209.

15. A method of treating hemophilia A in a subject in need thereof, comprising administering to said subject a dosage regimen selected according to any one of claims 1 to 14.

16. A device or system comprising a processor configured to provide dosing or PK information according to the method of any one of claims 1 to 14.

17. A data processing apparatus, device or system comprising a processor configured to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

18. 18. A data processing apparatus, device or system according to claim 17, wherein the processor is configured to implement the effanesoktocogalphapopPKmodel [A].

19. A computer program comprising instructions that, when said program is executed by a computer, cause said computer to carry out the method according to any one of claims 1 to 14.

20. A computer program comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF level or hematocrit level as covariates.

21. 21. The computer program of claim 20, wherein the efanesectocog alfa popPK model is efanesectocog alfa popPK model [A].

22. A computer readable medium comprising instructions that, when executed by a computer, cause the computer to perform the method of any one of claims 1 to 14.

23. A computer-readable medium comprising instructions that, when executed by a computer, cause the computer to implement a one-compartment efanesectocog alfa popPK model, wherein the efanesectocog alfa popPK model includes body weight as a covariate, and wherein the efanesectocog alfa popPK model does not include VWF levels or hematocrit levels as covariates.

24. 24. The computer-readable medium of claim 23, wherein the efanesectocog alfa popPK model is efanesectocog alfa popPK model [A].

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