For those like me [Geo] who are just learning of it, efanesoctocog alfa (“EFA,” ALTUVIIIO™), US FDA-approved in February of 2023 is Sanofi/Sodi’s extended half-life synthetic FVIII concentrate whose FVIII molecule is fused to a VWF fragment, thus extending the half-life to ~52 hours, requiring once-a-week infusions. Here is the FDA statement: Efanesoctocog alfa (ALTUVIIIOTM; [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl]), a von Willebrand factor (VWF) independent, recombinant DNA-derived Factor VIII (FVIII) concentrate, has been developed by Bioverativ Therapeutics, Inc (a Sanofi company) and Swedish Orphan Biovitrum AB (Sobi). Efanesoctocog alfa was approved in February 2023 in the USA for use in adults and children with hemophilia A (congenital FVIII deficiency) for routine prophylaxis to reduce the frequency of bleeding episodes; on-demand treatment and control of bleeding episodes; perioperative management of bleeding.
We received this March 11 2024 message from Heidi Hobbs: Hello! I was contacted by one of our oncology pharmacists about factor VIII [FVIII] testing for patients on efanesoctocog alfa (ALTUVIIIO™). She shared a paper cited below. Based on this study, the drug manufacturer recommends using a one-stage clotting assay [OSA] to measure FVIII activity. The package insert also states the FVIII level is overestimated by the chromogenic substrate assay [CSA] by approximately 2.5-fold, and if the CSA is used to divide the result by 2.5. However, the study included 51 OSA results from 14 PTT reagents and 42 CSA results from 8 kits, and to make their recommendation they combined results for all reagents, though the CV was wide. For the specific reagents we use, there were only 15 tests for the OSA and it underestimated FVIII activity by 30-40%. There were only 3 tests performed for the CSA kit we use, which showed a pretty consistent overestimation of 200%. Because of the way the recommendations were derived, with wide variability across the test results based on reagent type, using the recommended interpretation guidelines does not seem safe for patient care. In addition, we were told that the recommendation is to use the CSA during the time the patient is transitioning from emicizumab [Hemlibra™] to Altuviiio and divide the result by 2.5, but I do not have a study or literature to support this practice. I am wondering if you have any experience with Altuviiio and factor analysis for patient management. As a lab, we are uncomfortable with what we have been given and are not quite sure how to proceed and would appreciate any insight you can provide. Thanks.
The citation: Pipe S, Sadeghi-Khomami A, Konkle BA, Kitchen S, Negrier C, Liu M, Santagostino E, Willemze A, Abad-Franch L, Knobe K, Seth Chhabra E. A global comparative field study to evaluate the factor VIII activity of efanesoctocog alfa by one-stage clotting and chromogenic substrate assays at clinical haemostasis laboratories. Haemophilia 2024;30:214–23. doi: 10.1111/hae.14831. Epub 2023 Oct 30. PMID: 37902390.
I turned to several colleagues and received the following information:
From Ali Sadeghi-Khomami, PhD, Director of Research & Development, Precision BioLogic Inc.
Hi George, I was one of the authors of the article referenced here. Please note that the results presented in that article were from an in vitro global field study and it was only supposed to detect any significant difference in drug measurement by existing FVIII activity assays in the real lab setting. The study used spiked but uniformly made plasma samples to send around the world. It was neither a controlled study nor from patient-drawn blood samples. Thus, individual PK variations and clinical effects were out of scope.
Based on the details mentioned by Heidi, I figured SynthASil and Coatests are APTT-OSA and CSA of interest, respectively. In the supplementary information of the article [open access, click], more details could be found for assay-specific conversion factors that include the type of analyzer. For instance, if Coatest FVIII activity results from ACL TOP analyzer are divided by 3 (or ~2.5 as simplified in USPI), then the estimate of reference OSC activity by Actin FSL could be deduced. However, this still would be a rough estimate from an in vitro field study and the other limitations such as individual PK variation should be acknowledged in this approach.
If transitioning a patient from emicizumab (Hemlibra) to efanesoctocog alfa (ALTUVIIIO) is the goal, then a non-human-based FVIII CSA such as Coatest seems to be a reasonable choice. I am not aware of any direct study in this regard but in theory, unlike OSA and human CSA, the FVIII activity estimate of ALTUVIIIO by Coatest shouldn’t be impacted by emicizumab presence and the conversion estimate should be promising.
Currently, ALTUVIIIO plasma sample panels are available to North American labs that want to verify the suitability of their FVIII assay in drug activity measurement. There is still a need for clinical studies to show the commutability of various FVIII assay results between spiked in vitro plasma samples and blood draws from HA patients receiving medicine/s. Regards, Ali
From Bob Gosselin: Thanks for sharing, Ali.
All of the extended half-life [EHL] pharma companies did field studies for accessing factor activities using surrogate samples. We participated in 3–4 of those studies, and they provide a yardstick of what to see, not so much as the real world [although likely commutable] but differences between platforms. Methods for assessing drug potency is a hot topic in that arena. That said, local verification of performance should be entertained and hopefully external quality programs like ECAT will have some material from the companies that can be provided to interested labs. One EHL pharma provided a verification/validation “kit” at no cost to the customer.
My issue with all of these novel therapies is not with the savvy labs in hemophilia treatment centers but those non-academic/community/rural places that may serve either Hemophilia A or Hemophilia B HA/HB patients, but may also serve as stroke, trauma [etc] centers. The message, even in the prescribing information (PI), is often limited or misleading. It is highly unlikely these labs possess any OSA or Chromo assay, let alone have the wherewithal to assess combined Rx.
I would also suggest reading the FDA summary of characteristics for this drug [as well as any other drug of interest] which is available online, as well as any summary provided by the European Medicines Agency if the Rx is approved for use across the pond. These lengthy documents often hold gold nuggets of information that do not make it to the PI. Also try looking at Canadian monographs, UK?EMA and MIMS [Australia] PI as often, they too have PK/PD information that may not make it to the FDA-approved PI in the US.
Further challenges for the hemostasis laboratories: DOACs, more novel anticoagulants in the hopper, EHLs, HA/HB gene therapies, bypassing agents, and yet more to come. It is becoming evident that no single platform is able to address all of our needs.
Comment from Geo: I thank Bob and Dr. Ali for their thoughtful and comprehensive responses. To a medical laboratory scientist, the idea of treating the raw value with an arbitrary factor causes sleepless nights, however, it seems Heidi may be able to request calibration and control samples from Sanofi/Sobi.
Please see the attached “EFA” commentary provided on March 16, 2024, from Annette Bowyer and the attached BIVV001 commentary from Geoffrey Kershaw provided on March 17, 2024.
No comments here.