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Indirect Treatment Comparison of Damoctocog Alfa Pegol versus Turoctocog Alfa Pegol as Prophylactic Treatment in Patients with Hemophilia A
Vashi P, Batt K, Klamroth R, Mancuso ME, Majewska R, Tiede A, Mantovani LG
Journal of blood medicine. 2021;12:935-943
Abstract
PURPOSE To assess the efficacy and FVIII consumption of BAY 94-9027 versus N8-GP in prophylaxis in adolescent and adult patients with severe hemophilia A (HA). PATIENTS AND METHODS A systematic literature review was conducted to identify studies on the efficacy of BAY-94-9027 and N8-GP for prophylaxis in patients with HA aged ≥12 years without a history of inhibitors. Eight studies met systematic literature review inclusion criteria, but only data from PROTECT VIII on BAY 94-9027 and PATHFINDER 2 on N8-GP could be used for an indirect comparison. Matching-adjusted indirect comparison (MAIC) and simulated treatment comparison were performed. RESULTS No significant differences (unadjusted and adjusted) were observed in the mean annualized bleeding rate (ABR) for any bleed and proportion of patients with zero bleeds when comparing BAY 94-9027 to N8-GP. The adjusted treatment difference [incidence rate ratio (IRR)] in terms of ABR was 1.11 (95% CI, 0.85-1.44). The odds ratio (OR) of any bleed, measuring the relative effect of BAY 94-9027 versus N8-GP on the proportion of patients with zero bleeds, was 1.03 (95% CI, 0.60-1.77). FVIII consumption was significantly lower in BAY 94-9027 [mean adjusted difference=-1292.57 IU/kg/year (95% CI, ‒2152.44 to ‒432.70)]; a 26.7% reduction in consumption of BAY-94-9027. The results of the sensitivity analyses were similar to the main analysis for mean ABRs, percentages of patients with zero bleeds, and significant reduction in rFVIII consumption. For patients on BAY 94-9027 every-5-days and every-7-days, no differences versus every-4-days N8-GP were observed for the mean ABR for any bleed [IRR=0.90 (95% CI, 0.68‒1.20)] and proportion of patients with zero bleeds [OR=1.06 (95% CI, 0.56‒2.02)]. CONCLUSION BAY 94-9027 prophylaxis demonstrated 26.7% lower annual consumption when compared to N8-GP with similar efficacy in terms of ABR and percentage of patients with zero bleeds.
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Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: A randomized trial
Escuriola Ettingshausen C, Hegemann I, Simpson ML, Cuker A, Kulkarni R, Pruthi RK, Garly ML, Meldgaard RM, Persson P, Klamroth R
Research and practice in thrombosis and haemostasis. 2019;3(2):268-276
Abstract
Background and Objective: Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are extended half-life rFIX compounds. We report the first single-dose pharmacokinetic trial of N9-GP and rFIXFc. Patients/Methods: Paradigm 7 was a multicenter, open-label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9-GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one-stage clotting assays (SynthAFax for N9-GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity-time curve from 0 to infinity, dose-normalized to 50 IU/kg (AUC0-inf,norm). Results: Fifteen patients received study treatment. Based on FIX activity results from the one-stage clotting assays, estimated AUC0-inf,norm was significantly greater for N9-GP than rFIXFc (ratio: 4.39; P < 0.0001, based on a two-sided test on 5% significance level). In addition, N9-GP had a longer terminal half-life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose-normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound. Conclusions: In this comparison, N9-GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9-GP and rFIXFc. Registration: This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016-001149-25).
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Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: Safety and efficacy results from pathfinder 2 (randomized phase III trial)
Curry N, Albayrak C, Escobar M, Andre Holme P, Kearney S, Klamroth R, Misgav M, Negrier C, Wheeler A, Santagostino E, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2019
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Abstract
INTRODUCTION Turoctocog alfa pegol (N8-GP) is a site-specific, 40 kDa glycoPEGylated recombinant factor VIII (FVIII) product with an extended half-life. The comprehensive main phase of the pivotal pathfinder 2 trial showed N8-GP dosed every 4 days (Q4D) provided favourable safety and efficacy for preventing bleeds in 175 patients with haemophilia A. AIM AND METHODS We investigated the safety and efficacy of N8-GP prophylaxis when administered weekly (Q7D) for 24 weeks to patients with low bleeding rates in the pathfinder 2 extension trial. Patients (≥12 years) with ≤2 bleeds during the preceding 6 months of the pathfinder 2 main phase were eligible for randomization to receive N8-GP 50 IU/kg Q4D or 75 IU/kg Q7D. Safety and efficacy endpoints were incidence of FVIII inhibitors and annualized bleeding rate (ABR), respectively. RESULTS Fifty-five of 143 (38.5%) patients on prophylaxis who continued into the extension phase were randomized to receive 50 IU/kg Q4D (n = 17) or 75 IU/kg Q7D (n = 38). Nine patients in the Q7D cohort reverted to 50 IU/kg Q4D. No inhibitors were detected. In both cohorts, >50% of patients experienced no bleeds. Median ABR for overall, joint, spontaneous, traumatic and muscle was 0.00 for both cohorts. Overall estimated success rate for treating bleeding episodes was 87.5%; 94.7% of bleeds were controlled with ≤2 injections. CONCLUSIONS Weekly N8-GP was well tolerated and efficacious and may benefit selected "low bleeder" patients with haemophilia A.
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Matching-adjusted indirect comparisons of annualized bleeding rate and utilization of BAY 94-9027 versus three recombinant factor VIII agents for prophylaxis in patients with severe hemophilia A
Batt K, Gao W, Ayyagari R, Deschaseaux C, Vashi PB, Yao Z, Wang Y, Kessabi S, Klamroth R
Journal of blood medicine. 2019;10:147-159
Abstract
Background: BAY 94-9027 is an extended half-life recombinant factor VIII (rFVIII) that prevents bleeding in persons with hemophilia A at twice-weekly, 5-day, and 7-day dosing intervals. In rare diseases such as hemophilia, where small populations preclude head-to-head comparisons in randomized controlled trials, outcomes from different studies can be compared by matching-adjusted indirect treatment comparisons (MAICs) via matched summary statistics of individual patient data. This study compared MAIC-adjusted outcomes of BAY 94-9027 with other FVIII agents for prophylaxis of hemophilia. Methods: Weighted patient data from the BAY 94-9027 PROTECT VIII trial were used to compare annualized bleeding rates (ABRs), percentage of patients with zero bleeds, and factor utilization against published data on rFVIII-Fc fusion protein (rFVIIIFc), BAX 855, and recombinant antihemophilic factor/plasma/albumin-free method (rAHF-PFM). Results: After matching BAY 94-9027 and comparators, the mean BAY 94-9027 utilization was significantly lower than rFVIIIFc pre- and post-matching (66.2 vs 82.2 IU/kg/week; 66.5 vs 82.2 IU/kg/week; both P<0.001). Median BAY 94-9027 utilization (IU/kg/week) trended lower than BAX 855 (64.3 vs 87.4) and rAHF-PFM (2004 study: 64.0 vs 107.5; 2012 study: 63.6 vs 109.9). Mean ABRs and percentages of patients with zero bleeds were similar post-matching between BAY 94-9027 and comparators. Conclusion: BAY 94-9027 demonstrated similar MAIC-adjusted ABR with lower utilization than rFVIIIFc, BAX 855, and rAHF-PFM.
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Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial
Mannucci PM, Kempton C, Millar C, Romond E, Shapiro A, Birschmann I, Ragni MV, Gill JC, Yee TT, Klamroth R, et al
Blood. 2013;122((5):):648-57.
Abstract
Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.