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Clinical Trial
. 2021 Jun;19(6):1436-1446.
doi: 10.1111/jth.15270. Epub 2021 May 18.

Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort

K John Pasi  1 , Toshko Lissitchkov  2 , Vasily Mamonov  3 , Tim Mant  4   5 , Margarita Timofeeva  6 , Catherine Bagot  7 , Pratima Chowdary  8 , Pencho Georgiev  9 , Liana Gercheva-Kyuchukova  10 , Kate Madigan  11 , Huy Van Nguyen  11 , Qifeng Yu  12 , Baisong Mei  12 , Craig C Benson  12 , Margaret V Ragni  13   14
Affiliations
Clinical Trial

Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort

K John Pasi et al. J Thromb Haemost. 2021 Jun.

Abstract

Background: Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors.

Objectives: To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors.

Patients/methods: In this open-label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once-monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient-reported outcomes (exploratory).

Results: The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean [SEM]) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean [standard deviation] 69.4 [16.3] days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (-9.2 [2.9]) and physical health (-12.3 [3.9]) domain scores suggested clinically meaningful improvement.

Conclusions: Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.

Keywords: antithrombin; fitusiran; hemophilia; inhibitors; siRNA.

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Conflict of interest statement

K. J. Pasi received grants, personal fees, and nonfinancial support from Sanofi Genzyme and BioMarin; personal fees and nonfinancial support from Hoffmann‐La Roche, OctaPharma, Catalyst Biosciences, Pfizer, Novo Nordisk, Swedish Orphan Biovitrum AB, Takeda, Biotest AG, and Sigilon Therapeutics; grants from Uniqure NV; and personal fees from ApcinteX. T. Lissitchkov has nothing to disclose. V. Mamonov received fees from Alnylam Pharmaceuticals and Sanofi Genzyme for serving as the principal investigator on clinical trials. T. Mant is an employee of Iqvia who received fees from Alnylam Pharmaceuticals and Sanofi Genzyme for conduct of the study. Outside the submitted work, P. Chowdary received research funding and fees for attendance at advisory board meetings from Pfizer, Bayer AG, CSL Behring, Freeline, Novo Nordisk, Swedish Orphan Biovitrum AB; personal fees from BioMarin and Uniqure NV; and fees for attendance at advisory board meetings from Chugai, Hoffmann‐La Roche, Takeda, Sanofi Genzyme, and Spark Therapeutics. L. Gercheva‐Kyuchukova received research grants from Alnylam Pharmaceuticals, Baxter, Bayer AG, Celgene, Gilead, and Novartis; honoraria and consulting fees from AbbVie, Amgen, Hoffmann‐La Roche, Johnson & Johnson, Novartis, Pfizer, and Takeda; and travel support from Celgene. K. Madigan was an employee of Alnylam Pharmaceuticals at the time of the study and is now an employee of Syros Pharmaceutical, Inc. H. Van Nguyen is an employee of Alnylam Pharmaceuticals. Q. Yu was an employee of Sanofi at the time of the study and is now an employee of Albireo Pharma Inc. B. Mei and C. C. Benson are employees of Sanofi Genzyme. M. V. Ragni received research funding and fees for attending advisory board meetings from Alnylam Pharmaceuticals, Sanofi Genzyme, BioMarin, Bioverativ, and Spark Therapeutics; research funding from CSL Behring, Genentech‐Roche, and Sangamo; and the gift of trial drug and fees for attending advisory boards from Baxalta/Takeda. M. Timofeeva has nothing to disclose. C. Bagot has nothing to disclose. P. Georgiev has nothing to declare.

Figures

FIGURE 1
FIGURE 1
(A) Effect of fitusiran on AT activity. Mean (± SEM) percentage of AT activity relative to baselinea in participants with hemophilia A or B with inhibitors receiving fitusiran once monthly. (B) Mean (± SEM) plasma thrombin generation peak height (nmol/L) over time by fitusiran dose group. aAs baseline AT levels may vary between individuals, percentage of AT activity for each participant was calculated relative to individual participant baseline measurements. Baseline measurements are the average of all predose measurements within 60 days of first dose excluding optional predose PK visits. The mean of these individual AT activity measurements is presented. Abbreviations: AT, antithrombin; MDI, multiple dose with inhibitors; PK, pharmacodynamics; SEM, standard error of the mean
FIGURE 2
FIGURE 2
Post hoc analysis of thrombin generation associated with AT reduction in patients with hemophilia A or B with inhibitors. For all patients, at each time point an AT level and a corresponding thrombin generation measurement were recorded. All available thrombin generation values were associated with an AT activity level relative to baseline and were binned into AT lowering quartiles. Boxes denote median and interquartile ranges. Middle line in the boxes denote median values and top and bottom of the boxes represent the interquartile ranges. Minimum and maximum values are shown by the bars (excluding outliers). Healthy volunteer data were previously presented in Pasi et al. 28 Abbreviation: AT, antithrombin
FIGURE 3
FIGURE 3
ABR during monthly fitusiran treatment in individual participants with hemophilia A or B with inhibitors. Prestudy ABR was calculated as the occurrence of clinically significant bleeds based on 6‐month history multiplied by 2. Observation period ABR was estimated by the number of poststudy drug treatment bleeding episodes that occurred from day 29 until 8 weeks after the last dose of fitusiran. Abbreviation: ABR, annualized bleeding rate
See this image and copyright information in PMC

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