Abstract Number: PB0542
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: PROPEL primary data showed that targeting 8-12% factor VIII (FVIII) troughs results in fewer bleeds vs 1-3% troughs, which suggests personalized dosing can help control/prevent bleeding in patients without compromising the efficacy/safety of rurioctocog alfa pegol (TAK-660, BAX 855).
Aims: To explore the impact of pre-study treatment regimen (on-demand FVIII [OD] or prophylactic FVIII [PPx]) and annualized bleeding rate (ABR) on the efficacy of TAK-660 prophylaxis targeting 1-3% or 8-12% FVIII troughs.
Methods: Design, primary outcomes, and overall safety of PROPEL (NCT0285960) were previously reported; ethics committee approvals and patient informed consent were obtained. Patients aged 12-65 years with ABR ≥2 were randomized to 12 months’ pharmacokinetic (PK)-guided prophylaxis targeting 1-3% or 8-12% FVIII troughs (first 6 months: treatment adjustment). Subgroups analyzed: patients on previous OD, PPx with average ABR <5 before study start, and PPx with ABR ≥5 before study start. Outcomes in second 6 months: point estimates (95% CI) of mean for ABR and proportion of patients with zero ABR (total [all bleeds], spontaneous, spontaneous joint, injury related).
Results: In the 8-12% arm, total, spontaneous, and spontaneous joint ABRs were lower in all subgroups versus the 1-3% arm (Table 1). Injury-related ABR was lower in the 8-12% arm among previous OD patients and patients on previous PPx with ABR <5, but similar between arms in patients on previous PPx with ABR ≥5. In the 8-12% arm, the proportion of patients with zero total ABR was higher versus the 1-3% arm, regardless of pre-study regimen or ABR (Table 2).
|
Parameter |
On-demand FVIII treatment before study (OD) | Prophylactic FVIII treatment before study (PPx) | ||||
| FVIII trough level 1-3% |
FVIII trough level 8-12% |
Average ABR <5 in 12 months before enrollment | Average ABR ≥5 in 12 months before enrollment | |||
| FVIII trough level 1-3% |
FVIII trough level 8-12% |
FVIII trough level 1-3% |
FVIII trough level 8-12% |
|||
| Patients, n | 13 | 13 | 19 | 14 | 20 | 16 |
| Total ABR | 1.8 (1.0-3.3) | 0.3 (0.1-1.2) | 2.3 (1.4-3.8) | 0.5 (0.2-1.5) | 3.5 (2.2-5.5) | 2.3 (1.3-4.2) |
| Spontaneous ABR | 0.8 (0.3-1.9) | 0.1 (0.0-1.0) | 1.7 (0.8-3.3) | 0.3 (0.1-1.2) | 2.1 (1.1-4.2) | 1.1 (0.4-2.6) |
| Spontaneous joint ABR | 0.8 (0.3-2.0) | 0.0 | 1.1 (0.5-2.2) | 0.1 (0.0-1.0) | 1.4 (0.6-3.4) | 0.9 (0.3-2.6) |
| Injury-related ABR | 0.9 (0.3-2.4) | 0.2 (0.0-1.2) | 0.5 (0.2-1.2) | 0.2 (0.0-0.9) | 1.3 (0.6-2.6) | 1.2 (0.5-2.8)‡ |
| ABR, annualized bleeding rate; CI, confidence interval; FVIII, factor VIII; PPAS, per-protocol analysis set. *Point estimates and 95% CIs were obtained from a generalized linear model fitting a negative binomial distribution. †Patients in the PPAS completed the second 6 months of prophylaxis with no significant protocol deviations. ‡ One patient experienced 5 knee-related injuries in 6 months that contributed to the injury-related ABR in this subgroup. |
||||||
Point estimate (95% CI)* of mean for ABR in second 6 months stratified by pre-enrollment regimen and ABR (PPAS†).
|
Parameter |
On-demand FVIII treatment before study (OD) | Prophylactic FVIII treatment before study (PPx) | ||||
| FVIII trough level 1-3% |
FVIII trough level 8-12% |
Average ABR <5 in 12 months before enrollment | Average ABR ≥5 in 12 months before enrollment | |||
| FVIII trough level 1-3% |
FVIII trough level 8-12% |
FVIII trough level 1-3% |
FVIII trough level 8-12% |
|||
| Patients, n | 13 | 13 | 19 | 14 | 20 | 16 |
| Patients with total ABR=0, % | 46.2 (19.2-74.9) |
84.6 (54.6-98.1) |
42.1 (20.3-66.5) |
71.4 (41.9-91.6) |
35.0 (15.4-59.2) |
50.0 (24.7-75.3) |
| Patients with spontaneous ABR=0, % |
69.2 (38.6-90.9) |
92.3 (64.0-99.8) |
57.9 (33.5-79.7) |
85.7 (57.2-98.2) |
55.0 (31.5-76.9) |
68.8 (41.3-89.0) |
| Patients with spontaneous joint ABR=0, % | 69.2 (38.6-90.9) |
100.0 (NA) |
63.2 (38.4-83.7) |
92.9 (66.1-99.8) |
65.0 (40.8-84.6) |
81.3 (54.4-96.0) |
| Patients with injury-related ABR=0, % | 69.2 (38.6-90.9) |
92.3 (64.0-99.8) |
73.7 (48.8-90.9) |
85.7 (57.2-98.2) |
65.0 (40.8-84.6) |
56.3 (29.9-80.2) |
| ABR, annualized bleeding rate; CI, confidence interval; FVIII, factor VIII; NA, not applicable; PPAS, per-protocol analysis set. *Patients in the PPAS completed the second 6 months of prophylaxis with no significant protocol deviations. |
||||||
Point estimate (95% CI) of proportion of patients with zero bleeds in second 6 months stratified by pre-enrollment regimen and ABR (PPAS*).
Conclusions: Irrespective of pre-study regimen/ABR, targeting 8-12% FVIII troughs lowered bleeding rates. In patients on pre-study PPx with ABR ≥5, 50% and 35% in the 8-12% and 1-3% arms, respectively, achieved zero total bleeds. Across all pre-study PPx patients, 81-93% and 63-65% in the 8-12% and 1-3% arms, respectively, achieved zero spontaneous joint bleeds.
To cite this abstract in AMA style:
Escuriola-Ettingshausen C, Escobar M, Windyga J, Zulfikar B, Tangada SD, Engl W, Honauer I, Lee H-, Klamroth R. Looking Beyond Fixed-Dose Rurioctocog Alfa Pegol Prophylaxis: Post Hoc Analysis of PK-guided Regimens from the PROPEL Phase 3 Study [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/looking-beyond-fixed-dose-rurioctocog-alfa-pegol-prophylaxis-post-hoc-analysis-of-pk-guided-regimens-from-the-propel-phase-3-study/. Accessed October 1, 2023.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/looking-beyond-fixed-dose-rurioctocog-alfa-pegol-prophylaxis-post-hoc-analysis-of-pk-guided-regimens-from-the-propel-phase-3-study/