Abstract Number: PB0920
Meeting: ISTH 2020 Congress
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.
|Parameter||FVIII trough level 1-3% (n=52)||FVIII trough level 8-12% (n=43)|
|FVIII t1/2 ||6 to <12 h||12 to <18 h||18 to <36 h||6 to <12 h||12 to <18 h||18 to <36 h|
|Total ABR||3.53 (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 ABR||2.79 (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 ABR||1.97 (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 ABR||0.95 (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).]
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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