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 (t_½) and dosing regimens. PROPEL patients with shorter FVIII t_½ 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 t_1/2	6 to <12 h	12 to <18 h	18 to <36 h	6 to <12 h	12 to <18 h	18 to <36 h
Patients, n	12	31	9	13	23	7^§
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; t_1/2, 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 t_1/2 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 t_1/2 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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