In the afternoon session "Haemophilia in Adults" at this year's GTH, results from the randomized prophylaxis phase III PROPEL study were presented. The study investigated the safety and efficacy of Rurioctocog alfa pegol in pharmacokinetic (PK)-guided prophylaxis targeting two different FVIII trough levels in previously treated patients. The results of the PROPEL study show zero rates of total bleeding and spontaneous joint bleeding that have not been reported by people with hemophilia A before.
The prophylactic FVIII replacement therapy is the current standard for the treatment of patients with severe hemophilia A. Prophylaxis with recombinant Extended Half-Life Factor VIII (EHL-FVIII), Rurioctocog alfa pegol, which targets an FVIII trough level of ≥ 1%, is effective and well tolerated in patients with severe hemophilia A. The prophylaxis with recombinant EHL-FVIII, Rurioctocog alfa pegol, which targets an FVIII trough level of ≥ 1%, is effective and well tolerated in patients with severe hemophilia A. Evidence to date suggests that an FVIII trough level of 1% does not prevent bleeding in all patients and that the annual bleeding rate (ABR) is close to zero when the FVIII level is ≥10%.
In order to determine the effects of achieving higher trough levels and increasing FVIII exposure, the PROPEL study was conducted to:
Eligible individuals had an FVIII activity of <1%, an ABR of ≥2 and switched from an earlier study or were 12-65 years old and had ≥150 exposure days with plasma or recombinant FVIII. After initial PK assessments, subjects received PK-guided prophylaxis for 12 months, targeting FVIII trough levels of 1-3% (low) or 8-12% (high).
The primary result was the percentage of subjects with ABR = 0 (all bleeding) during the second 6 months. Secondary endpoints included total ABR, spontaneous ABR and common ABR (annualized joint bleed rate or AJBR), and adverse events (AE).
Total-ABR (all bleedings) in the groups with low and high trough levels show a mean (SD) of 3.6 (7.3.) and 1.6 (3.3.) and a median (interquartile range or IQR) of 2.0 (4.0) and 0.0 (2.0).
In no treatment with Rurioctocog alfa pegol were deaths, thromboembolic events or severe allergic reactions observed, and no AE led to discontinuation. In a patient with a high FVIII trough level in the arm, there was a severe AE associated with Rurioctocog alfa pegol.
There was also a positive inhibitor test result in the Bethesda assay (0.6 BU) at week 8, which was not confirmed in subsequent inhibitor tests. Anti-FVIII-binding antibodies were negative for this patient during the entire study period. Furthermore, there was no impact on the PK, with a constant low being observed throughout the period.
PK-guided Rurioctocog alfa pegol prophylaxis, targeting high (8 - 12%) versus low (1 - 3%) FVIII trough levels, resulted in a consistently lower ABR and a higher proportion of patients with a total ABR = 0 overall. Similar differences were observed for spontaneous BR and joint ABR (AJBR). In an FVIII profile associated with a tumor value of 8-12%, 66% of patients achieved total ABR = 0, 84% achieved spontaneous ABR = 0, and 90% achieved spontaneous AJBR = 0. The AE profiles of both treatment arms were comparable and consistent with previous studies.
"The study confirms the importance of personalized prophylaxis for people with hemophilia," said Dr. Robert Klamroth, Head of the Department of Internal Medicine Angiology and Coagulation Disorders and Director of the Comprehensive Care Hemophilia Treatment Center and the Department of Hemostasis and Thrombosis at the Vivantes Hospital in Berlin. "The results indicate that the actual FVIII trough levels need to be measured. There is a clear trend that if we keep FVIII trough levels in a higher range, better outcomes for patients can be achieved, including improved bleeding protection that can help more patients stop bleeding. "
The data suggest that by optimizing the FVIII profiles, the 8-12% through level can be consistently achieved through PK-guided dosing and further personalization of treatment for patients with hemophilia A should be considered.
Further data of the study, e.g. the number of anti-PEG antibodies of the participating patients, will be presented at ISTH 2019 in Melbourne from 6 - 10 July.
1. Klamroth, R. (Berlin). SY17-6-AB - Results from a phase 3, randomized, multicentre study of Rurioctocog alfa pegol PK-Guided prophylaxis targeting 2 FVIII trough levels in patients with severe hemophilia a (Propel Study). IN: Symposium, Room II + III. Haemophilia adults. 01.03.2019, 14:45 - 16:15. 63rd Annual Meeting of the Society of Thrombosis and Haemostasis Research, Berlin, Germany. 27 Feb. - 2 Mar., 2019.
2. Takeda Announces Results from First-of-Its Child Phase IIIb/IV Trial PROPEL - a Randomized PK-Guided Prophylaxis Study Evaluating Higher Factor VIII Levels in Hemophilia A- at EAHAD 2019 February 06, 2019 01:00 AM Eastern Standard Time. Published: www.businesswire.com