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Personalizing Prophylaxis with Rurioctocog Alfa Pegol in Previously Treated Patients with Severe Hemophilia A: Outcomes from the Phase 3b CONTINUATION and Phase 3 PROPEL Studies

C. Escuriola-Ettingshausen1, R. Klamroth2, M. Escobar3, E.S. Mullins4, O. Stasyshyn5, S. Tangada6, W. Engl7, I. Honauer8, H.-Y. Lee8, P. Chowdary9, J. Windyga10

1Hamophilie-Zentrum Rhein Main, Mörfelden-Walldorf, Germany, 2Vivantes Klinikum im Friedrichshain, Berlin, Germany, 3University of Texas Health Science Center at Houston, Houston, United States, 4University of Cincinnati College of Medicine and Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, United States, 5Academy of Medical Sciences of Ukraine, Lviv, Ukraine, 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, 9Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, United Kingdom, 10Institute of Hematology and Transfusion Medicine, Department of Hemostasis Disorders and Internal Medicine, Warsaw, Poland

Abstract Number: PB0920

Meeting: ISTH 2020 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Prophylaxis with rurioctocog alfa pegol (TAK-660, SHP660, BAX 855) using fixed dose (FD) 40-50 IU/kg twice-weekly to achieve >1% factor VIII (FVIII) troughs is effective and well tolerated in previously treated patients with hemophilia A. Recent data suggest personalizing dosing can better control/prevent bleeds without compromising TAK-660 efficacy or safety.

Aims: To explore potential benefits of personalized TAK-660 prophylaxis by evaluating data on extended FD or pharmacokinetic (PK)-tailored dosing from 2 studies.

Methods: Design and primary outcomes of CONTINUATION (NCT01945593) and PROPEL (NCT0285960) were previously reported; ethics committees’ approval and patient informed consent obtained. CONTINUATION patients aged ≥12 years with a spontaneous annualized bleeding rate (ABR)=0 during 6 months’ TAK-660 prophylaxis could switch from twice-weekly to extended FD prophylaxis (every 5 days [q5d], subsequently q7d). PROPEL patients aged 12-65 years were randomized to 12 months’ PK-guided prophylaxis targeting 1-3% or 8-12% FVIII troughs.

Results: In CONTINUATION, point estimates of mean ABRs were low across all FD regimens of twice-weekly, q5d and q7d (total ABR: 2.2 [n=186], 2.1 [n=56], 2.7 [n=15]; spontaneous ABR: 1.2 [n=186], 1.3 [n=56], 1.8 [n=15]). In PROPEL, lower ABRs and higher ABR=0 rates were achieved and maintained with 8-12% versus 1-3% FVIII troughs; TAK-660 consumption varied but overlapping ranges between arms reflect variability in patient FVIII half-life (t½) and dosing regimens. PROPEL patients with shorter FVIII t½ had better bleed prevention with 8-12% versus 1-3% troughs (Table). Lower injury-related ABRs in PROPEL were observed during periods of FVIII activity ≥20% (Figure). TAK-660 safety profiles in CONTINUATION and PROPEL were consistent with earlier studies.

Conclusions: These results support the feasibility and efficacy of personalized TAK-660 prophylaxis by extending the FD interval or targeting elevated FVIII levels with PK-tailored dosing. These benefits may be especially important for patients requiring higher FVIII activity levels because of active lifestyles and increased risk of injury-related bleeds.

ParameterFVIII trough level 1-3% (n=52)FVIII trough level 8-12% (n=43)
FVIII t1/2 ‡6 to <12 h12 to <18 h18 to <36 h6 to <12 h12 to <18 h18 to <36 h
Patients, n1231913237§
Total ABR3.53 (2.25-5.53)2.48 (1.59-3.86)1.48 (0.59-3.68)0.66 (0.26-1.64)1.04 (0.54-2.01)1.65 (0.58-4.74)
Spontaneous ABR2.79 (1.63-4.77)0.95 (0.43-2.07)1.20 (0.49-2.94)0.28 (0.07-1.14)0.58 (0.21-1.59)0.49 (0.11-2.22)
Spontaneous joint ABR1.97 (1.11-3.50)0.54 (0.18-1.60)0.73 (0.23-2.26)0.15 (0.02-1.07)0.30 (0.07-1.26)0.18 (0.02-1.93)
Injury-related ABR0.95 (0.35-2.57)1.29 (0.75-2.22)0.13 (0.01-3.88)0.46 (0.13-1.61)0.41 (0.16-1.08)2.13 (0.30-14.97)
ABR, annualized bleeding rate; FVIII, factor VIII; PPAS, per-protocol analysis set; t1/2, half-life. Values are point estimates (95% CI) unless otherwise indicated. *Point estimates and 95% CIs were obtained from a generalized linear model fitting a negative binomial distribution. †Patients in the PPAS completed second 6 months of prophylaxis with no significant protocol deviations. ‡FVIII t1/2 category determined by one-stage clotting assay. §Includes 1 patient who experienced 5 injury-related knee bleeds in 6 months, which had a pronounced effect on total ABR.

[Table. Point estimates (95% CI)* of mean ABRs by baseline FVIII t1/2 in PROPEL (second 6-month study period; PPAS†).]


[Figure. Injury-related ABR by FVIII activity level in PROPEL (12-month study period; FAS).*]

To cite this abstract in AMA style:

Escuriola-Ettingshausen C, Klamroth R, Escobar M, Mullins ES, Stasyshyn O, Tangada S, Engl W, Honauer I, Lee H-, Chowdary P, Windyga J. Personalizing Prophylaxis with Rurioctocog Alfa Pegol in Previously Treated Patients with Severe Hemophilia A: Outcomes from the Phase 3b CONTINUATION and Phase 3 PROPEL Studies [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/personalizing-prophylaxis-with-rurioctocog-alfa-pegol-in-previously-treated-patients-with-severe-hemophilia-a-outcomes-from-the-phase-3b-continuation-and-phase-3-propel-studies/. Accessed March 3, 2021.
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