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CC BY-NC-ND 4.0 · Thromb Haemost
DOI: 10.1055/s-0044-1787734
Coagulation and Fibrinolysis

Field Study and Correlative Studies of Factor IX Variant FIX-R338L in Participants Treated with Fidanacogene Elaparvovec

Debra D. Pittman   *
1   Rare Disease Research Unit, Pfizer Inc., Cambridge, Massachusetts, United States
,
Charles Carrieri
2   Pfizer Inc., New York, New York, United States
,
Holly Soares   *
2   Pfizer Inc., New York, New York, United States
,
John McKay
3   Pfizer Inc., Groton, Connecticut, United States
,
Charles Y. Tan
3   Pfizer Inc., Groton, Connecticut, United States
,
John Z. Liang   *
2   Pfizer Inc., New York, New York, United States
,
Swapnil Rakhe   *
1   Rare Disease Research Unit, Pfizer Inc., Cambridge, Massachusetts, United States
,
Jean-Claude Marshall   **
3   Pfizer Inc., Groton, Connecticut, United States
,
John E. Murphy   ***
1   Rare Disease Research Unit, Pfizer Inc., Cambridge, Massachusetts, United States
,
Puneet Gaitonde
4   Pfizer Inc., Cambridge, Massachusetts, United States
,
Jeremy Rupon
5   Pfizer Inc., Collegeville, Pennsylvania, United States
› Author Affiliations Funding This study was sponsored by Pfizer.
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Abstract

Background Fidanacogene elaparvovec, an adeno-associated virus-based gene therapy vector expressing the high-activity factor IX (FIX) variant FIX-R338L, is in development for hemophilia B. One-stage clotting (OS) assays and chromogenic substrate (CS) assays are commonly used to measure FIX-R338L variant activity. Data from ongoing trials suggest FIX activity varies between different OS and CS assays.

Material and Methods To better understand FIX-R338L activity in clinical samples, an international multisite field study was conducted across a central laboratory and 18 local laboratories, using standard protocols, reagents, and instrumentation, with individual participant samples from a phase 1/2a study of fidanacogene elaparvovec.

Results Unlike the wild-type FIX control, FIX-R338L activity was higher with the OS silica-based assay versus OS ellagic acid–based and CS assays. Variation in FIX activity was greater at the lowest activity levels. Activated FIX (FIXa) in plasma could result in higher OS assay activity or increased thrombin generation, which could overestimate FIX activity. However, FIXa was not detected in the participant samples, indicating that it was not contributing to the OS assay differences. Since individuals on gene therapy may receive exogenous replacement FIX products, replacement products were spiked into patient plasma samples to target a therapeutic concentration. Exogenous FIX was additive to endogenous FIX-R338L, with no interference from FIX-R338L.

Conclusion These results demonstrate FIX-R338L activity can be measured with OS and CS assays in clinical laboratories and provide insight into assay variability when measuring FIX with endogenously produced FIX-R338L. The findings may help establish best practices for measuring FIX-R338L activity (Clinicaltrials.gov identifier: NCT02484092).

Keywords

biological assays - blood coagulation tests - factor IX - gene therapy - hemophilia B

Data Availability Statement

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.


Authors' Contribution

All authors had full access to the data, and all authors contributed to data interpretation and the drafting, critical review, and revision of the manuscript. All authors granted approval of the final manuscript for submission.


* At the time of study conduct.


** Current affiliation: Moderna, 200 Technology Square, Cambridge, MA 02139, United States


*** Current affiliation: Arbor Biotechnologies, 20 Acorn Park Drive, Cambridge, MA, 02140, United States


Supplementary Material



Publication History

Received: 14 December 2023

Accepted: 04 May 2024

Article published online:
11 June 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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