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BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A
Konkle BA, Shapiro AD, Quon DV, Staber JM, Kulkarni R, Ragni MV, Chhabra ES, Poloskey S, Rice K, Katragadda S, et al
The New England journal of medicine. 2020;383(11):1018-1027
Abstract
BACKGROUND Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).
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PERSEPT 1: a phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding
Wang M, Lawrence JB, Quon DV, Ducore J, Simpson ML, Boggio LN, Mitchell IS, Yuan G, Alexander WA, Schved JF
Haemophilia : the Official Journal of the World Federation of Hemophilia. 2017;23((6):):832-843
Abstract
INTRODUCTION Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. AIM: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). METHODS A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 mug/kg or 225 mug/kg initial doses with 75 mug/kg subsequent doses by schedule were administered until clinical response. RESULTS The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 mug/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 mug/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. CONCLUSION The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.
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A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management
Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, Patrone L, Wong WY, Prophylaxis Study Group
Journal of Thrombosis and Haemostasis. 2012;10((3):):359-67.
Abstract
BACKGROUND Prophylaxis with factor (F)VIII is considered the optimal treatment for managing hemophilia A patients without inhibitors. OBJECTIVES To compare the efficacy of two prophylaxis regimens (primary outcome) and of on-demand and prophylaxis treatments (secondary outcome), and to continue the evaluation of immunogenicity and overall safety of the ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (rAHF-PFM). PATIENTS/METHODS Previously on-demand-treated patients aged 7-59 years (n = 66) with FVIII levels <= 2% received 6 months of on-demand treatment and then were randomized to 12 months of either standard (20-40 IU kg(-1) every other day) or pharmacokinetic (PK)-tailored (20-80 IU kg(-1) every third day) prophylaxis, both regimens intended to maintain FVIII trough levels at or above 1%. Efficacy was evaluated in terms of annualized bleeding rates (ABRs). As subjects were first treated on-demand and then on prophylaxis, statistical comparisons between these treatments were paired. RESULTS Twenty-two (33.3%) subjects on prophylaxis experienced no bleeding episodes, whereas none treated on-demand were free from an episode of bleeding. ABRs for the two prophylaxis regimens were comparable, whereas differences between on-demand and either prophylaxis were statistically significant (P < 0.0001): median (interquartile range [IQR]) ABRs were 43.9 (21.9), 1.0 (3.5), 2.0 (6.9) and 1.1 (4.9) during on-demand treatment, standard, PK-tailored and any prophylaxis, respectively. There were no differences in FVIII consumption or adverse event rates between prophylaxis regimens. No subject developed FVIII inhibitors. CONCLUSIONS The present study demonstrates comparable safety and effectiveness for two prophylaxis regimens and that prophylaxis significantly reduces bleeding compared with on-demand treatment. PK-tailored prophylaxis offers an alternative to standard prophylaxis for the prevention of bleeding. 2011 International Society on Thrombosis and Haemostasis.
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Pharmacokinetic properties of IB1001, an investigational recombinant factor IX, in patients with haemophilia B: repeat pharmacokinetic evaluation and sialylation analysis
Martinowitz U, Shapiro A, Quon DV, Escobar M, Kempton C, Collins PW, Chowdary P, Makris M, Mannucci PM, Morfini M, et al
Haemophilia. 2012;18((6):):881-7.
Abstract
IB1001 trenacog alfa is an investigational recombinant factor IX (FIX) for the treatment and prevention of bleeding in individuals with haemophilia B. To compare the pharmacokinetics (PK) of IB1001 with nonacog alfa in individuals with haemophilia B and to assess the relationship between sialylation and PK of IB1001 (NCT00768287). A randomized, double-blind, non-inferiority, cross-over study conducted in participants aged >= 12 years weighing >= 40 kg, with severe or moderately severe haemophilia B (FIX activity <= 2 IU dL (-1) ). PK parameters were derived using observed FIX concentration levels and actual PK sampling times, and repeated in a subset of participants who had received IB1001 prophylaxis for 4-18 months. A retrospective analysis was conducted in subgroups according to the sialylation levels of IB1001 (50.8, 57.8-59.0%, or 71.7%). In the 32 adolescent and adult males evaluated, there were no clinically meaningful differences in PK parameters between those receiving IB1001 75 IU kg (-1) or nonacog alfa. The lower limit of the one-sided 95% confidence interval for the ratio of AUC (0-t) and AUC (0-) (IB1001/nonacog alfa) was 0.90, establishing non-inferiority. Terminal phase half-lives were similar (29.7 +/- 18.2 h for IB1001 and 33.4 +/- 21.2 h for nonacog alfa). The PK results were stable for up to 18 months of IB1001 exposure; the impact of sialylation levels was not clinically meaningful. There were no clinically meaningful PK differences between IB1001 and nonacog alfa. IB1001 was well tolerated and without safety concerns. The non-inferiority of IB1001 to nonacog alfa supports IB1001 becoming a useful alternative recombinant agent for the management of haemophilia B. 2012 Blackwell Publishing Ltd.