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Efficacy and Target Joint Resolution with Pharmacokinetic-Guided Rurioctocog Alfa Pegol Prophylaxis Targeting Two Factor VIII trough Levels in Patients with Severe Hemophilia A: Post-Hoc Analysis of the Phase 3 PROPEL Trial

P. Collins1, J. Windyga2, M. Escobar3, H.M. Ibrahim4, J.C.M. Lam5, S.D. Tangada6, W. Engl7, I. Honauer8, A. Fernandez8, H.-Y. Lee8, R. Klamroth9, C. Escuriola-Ettingshausen10

1Cardiff University, School of Medicine, Cardiff, Wales, United Kingdom, 2Institute of Hematology and Transfusion Medicine, Department of Hemostasis Disorders and Internal Medicine, Warsaw, Poland, 3University of Texas Health Science Center at Houston, Houston, TX, United States, 4Hospital Kuala Lumpur, Kuala Lumpur, Malaysia, 5KK Women's and Children's Hospital, Singapore, Singapore, 6Baxalta US Inc., a Takeda Company, Cambridge, United States, 7Baxalta Innovations GmbH, a Takeda Company, Vienna, Austria, 8Shire International GmbH, a Takeda Company, Zurich, Switzerland, 9Vivantes Klinikum im Friedrichshain, Berlin, Germany, 10Hamophilie-Zentrum Rhein Main, Mörfelden-Walldorf, Germany

Abstract Number: PB0921

Meeting: ISTH 2020 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Primary results of PROPEL (NCT02585960) demonstrated clinical benefits of targeting elevated factor VIII (FVIII) troughs with rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) prophylaxis with no change in safety profile.

Aims: Assess efficacy and target joint (TJ) resolution with pharmacokinetic (PK)-guided TAK-660 prophylaxis in a post-hoc analysis.

Methods: PROPEL study design was previously reported (Klamroth et al., RPTH 2019); ethics committees’ approval and patient informed consent obtained. Patients were randomized to PK-guided TAK-660 prophylaxis targeting FVIII troughs of 1-3% (reference) or 8-12% (elevated). TJ was defined as a joint with ≥4 bleeds during any consecutive 6 months. Outcomes evaluated: total annualized bleeding rate (ABR; all bleeds) according to patients’ TJ status at screening and TJ ABR (per-protocol analysis set; second 6 months completed, no significant protocol deviations); course of TJs in treated patients with ≥6-months’ observation (full analysis set; randomized, ≥1 prophylactic dose received).

Results: In patients with 0 (n=26) and ≥1 (n=69) TJs, respectively, mean total ABR point estimates (95% CI) were 2.6 (1.5-4.6) and 2.4 (1.6-3.5) in 1-3% arm and 1.5 (0.6-3.5) and 0.9 (0.5-1.6) in 8-12% arm (Table 1). Spontaneous and spontaneous joint ABRs were also lower in 8-12% versus 1-3% arm irrespective of TJ status; injury-related ABR was slightly higher in 8-12% arm with no TJs and lower with ≥1 TJ at screening. Mean TJ ABRs (both arms) decreased during 12-months’ treatment (Table 2). In 112/115 evaluable patients, TJs resolved in all but 1 patient per arm after 6 months’ prophylaxis.

Conclusions: Targeting 8-12% versus 1-3% FVIII troughs was associated with reduced bleeding into TJs, reduced ABR irrespective of baseline TJ status, and TJ resolution within the first 6 months in all but 1 patient per arm. Results show the clinical benefit of elevating FVIII troughs with TAK-660 for TJ resolution, an important consideration for joint health in hemophilia A.

TJ statusPoint estimate (95% CI)* of mean ABRFVIII trough level 1-3%FVIII trough level 8-12%
No TJs (1-3% arm, n=16; 8-12% arm, n=10)Total ABR2.6 (1.5-4.6)1.5 (0.6-3.5)
 Spontaneous ABR1.3 (0.6-2.5)0.1 (0.0-1.1)
 Spontaneous joint ABR1.2 (0.7-2.3)0.0 (NC)
 Injury-related ABR0.8 (0.3-2.2)1.0 (0.3-3.5)
≥1 TJ (1-3% arm, n=36; 8-12% arm, n=33)Total ABR2.4 (1.6-3.5)0.9 (0.5-1.6)
 Spontaneous ABR1.3 (0.7-2.3)0.5 (0.2-1.1)
 Spontaneous joint ABR1.2 (0.6-2.4)0.5 (0.2-1.3)
 Injury-related ABR1.1 (0.6-1.9)0.4 (0.2-1.0)
ABR, annualized bleeding rate; FVIII, factor VIII; NC, not calculable due to no events in the 8-12% arm; TJ, target joint. *Point estimates and 95% CIs were obtained from a generalized linear model fitting a negative binomial distribution.

[ABR by TJ status at screening: second 6-month study period in the per-protocol analysis set.]

Study periodParameterFVIII trough level 1-3% (n=52)FVIII trough level 8-12% (n=43)
First 6 monthsTJ ABRMean (SD)0.5 (1.4)0.7 (2.3)
  Median (Q1-Q3)0.0 (0.0-0.0)0.0 (0.0-0.0)
Second 6 monthsTJ ABRMean (SD)0.1 (0.6)0.2 (1.3)
  Median (Q1-Q3)0.0 (0.0-0.0)0.0 (0.0-0.0)
ABR, annualized bleeding rate; FVIII, factor VIII; Q, quartile; TJ, target joint.

[ABR of TJ bleeds: first and second 6-month study periods in the per-protocol analysis set]

To cite this abstract in AMA style:

Collins P, Windyga J, Escobar M, Ibrahim HM, Lam JCM, Tangada SD, Engl W, Honauer I, Fernandez A, Lee H-, Klamroth R, Escuriola-Ettingshausen C. Efficacy and Target Joint Resolution with Pharmacokinetic-Guided Rurioctocog Alfa Pegol Prophylaxis Targeting Two Factor VIII trough Levels in Patients with Severe Hemophilia A: Post-Hoc Analysis of the Phase 3 PROPEL Trial [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/efficacy-and-target-joint-resolution-with-pharmacokinetic-guided-rurioctocog-alfa-pegol-prophylaxis-targeting-two-factor-viii-trough-levels-in-patients-with-severe-hemophilia-a-post-hoc-analysis-of-t/. Accessed March 3, 2021.
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