Allen, G

Li, L

Mahlangu, JN

Pasi, J

Pierce, GF

Quon, DV

Shapiro, AD

Zhu, Y

Blood

English

Queen Mary Research Online

Predicting FVIII Activity in Patients Who Use Recombinant FVIII Fc FusionProtein for Prophylaxis and Treatment of Bleeding EpisodesQuon, DV; Mahlangu, JN; Shapiro, AD; Pasi, J; Zhu, Y; Pierce, GF; Li, L; Allen, G       For additional information about this publication click this link.http://qmro.qmul.ac.uk/jspui/handle/123456789/7668   Information about this research object was correct at the time of download; we occasionallymake corrections to records, please therefore check the published record when citing. Formore information contact scholarlycommunications@qmul.ac.ukAmerican Society  of Hematology (ASH)56th Annual MeetingDecember 6-9, 2014 San Francisco, California*Presenting author.Predicting FVIII Activity in Patients Who Use Recombinant FVIII Fc Fusion Protein for Prophylaxis and Treatment of Bleeding EpisodesDoris Quon,1,* Johnny Mahlangu,2 Amy Shapiro,3 John Pasi,4 Glenn F Pierce,5 Shuanglian Li,5 Elisa Tsao,5 Geoffrey Allen,5 Brian Robinson51Orthopaedic Hospital, Hemophilia Treatment Center, Los Angeles, CA, USA; 2University of the Witwatersrand, Faculty of Health Sciences, Johannesburg, South Africa;  3Indiana Hemophilia and Thrombosis Center, Indianapolis, IN, USA; 4Barts and The London School of Medicine and Dentistry, London, UK; 5Biogen Idec, Cambridge, MA, USA1522INTRODUCTION•   Prophylaxis with replacement factor VIII (FVIII) is the standard of care for people with hemophilia A, and is known to reduce the frequency of bleeding episodes and prevent arthropathy1•   However, despite prophylactic factor replacement, patients may still be at risk for developing bleeding episodes2•   The Phase 3 A-LONG study demonstrated the prolonged half-life of recombinant factor VIII Fc fusion protein (rFVIIIFc; geometric mean, 19.0 hours) relative to recombinant FVIII (rFVIII; geometric mean, 12.4 hours), and the efficacy and safety of rFVIIIFc for routine prophylaxis and treatment of bleeding in people with severe hemophilia A3•   In the A-LONG study (including participants receiving either episodic or prophylactic treatment with rFVIIIFc), most acute bleeding episodes were resolved with a single rFVIIIFc infusion (87.3%), and the majority of participants rated their response to treatment as “excellent” or “good” (77.6%)3 –  A subanalysis of the efficacy of rFVIIIFc for the treatment of bleeding only in subjects receiving rFVIIIFc prophylaxis has not been performed to date  –  The magnitude of the peak factor activity following treatment of a bleeding episode and/or scheduled prophylaxis in subjects receiving rFVIIIFc prophylaxis has not yet been evaluatedOBJECTIVES•   The purpose of this post hoc analysis was to assess the efficacy of rFVIIIFc used for the treatment of bleeding in participants who received rFVIIIFc prophylaxis in the A-LONG study •   In addition, a population pharmacokinetic model of rFVIIIFc was used to predict FVIII activity in participants who use rFVIIIFc to treat bleeding episodes in close proximity to their next scheduled prophylaxis dose METHODSStudy Design and Participants•   The A-LONG study was a Phase 3, open-label, multicenter, partially randomized study (ClinicalTrials.gov Identifier: NCT01181128)•   This study included male participants ≥12 years of age with severe hemophilia A  (<1 IU/dL [1%] endogenous FVIII activity or severe genotype) who had been previously treated prophylactically, or episodically with ≥12 bleeding events in the 12 months prior to the study; participants with a history of inhibitors were excluded –  Participants were enrolled into 1 of 3 treatment groups: individualized prophylaxis (twice-weekly rFVIIIFc dosing; 25 IU/kg on Day 1 and 50 IU/kg on Day 4 to start, followed by 25–65 IU/kg every 3–5 days to maintain trough levels between 1–3 IU/dL), weekly prophylaxis (65 IU/kg rFVIIIFc once weekly), or episodic treatment  (10–50 IU/kg rFVIIIFc as needed for the treatment of bleeding episodes)  ∙  This analysis included only participants in A-LONG who received rFVIIIFc prophylaxis (enrolled in the individualized prophylaxis or weekly prophylaxis groups) •   Acute bleeding episodes were treated with 10 to 50 IU/kg of rFVIIIFc; dosing was based on the participant’s clinical condition, type and severity of the bleeding event, and the participant’s previous dosing history for a similar bleeding episode (Table 1)Outcomes•   Outcomes evaluated in this analysis included: number of bleeding episodes, location and type of bleeds, the average dose per infusion required to treat a bleed, the number of infusions required to resolve a bleed, participants’ assessment of response to treatment (recorded within 8–12 hours of first infusion), and safety  Statistics•   Descriptive statistics were used to provide the median and interquartile range (IQR). Frequency and percent were summarized categorically Pharmacokinetic Simulations•   A previously validated 2-compartment population pharmacokinetic model of rFVIIIFc,4 developed based on activity-time profiles from participants enrolled in the Phase 1/2a study of rFVIIIFc (n = 16)5 and the A-LONG study (n = 164),3 was used to predict FVIII activity levels in 1,000 hypothetical patients •   FVIII activity was modeled under 2 scenarios in which a 25 IU/kg dose of rFVIIIFc was used to treat a bleeding episode 24 hours before a scheduled prophylactic dose for patients at steady state on a regimen of 50 IU/kg every 3 or 4 days –  A dose of 25 IU/kg was selected to approximate the median dose per infusion used to treat a bleed –  Twenty-four hours is likely to be the closest proximity to a scheduled prophylaxis dose that a separate dose would be used to treat a bleeding episode –  The median total weekly prophylactic dose in Arm 1 of the A-LONG study was  77.9 IU/kg.3  For this modeling exercise, the dose and intervals used were chosen because 50 IU/kg was one of the starting doses in A-LONG, 4 days was one of the starting interval lengths, and 3 days was the shortest interval used in A-LONGRESULTSStudy Population•   Demographic and baseline characteristics in this study population were representative of a population with severe hemophilia A (Table 2).  Additionally, most participants in the individualized prophylaxis and weekly prophylaxis groups reported similar or increased physical activity with the use of rFVIIIFc on-studyBleeding Episodes by Type and Location•   In the individualized prophylaxis group, 209 bleeding episodes were reported in  64 participants (median annualized bleeding rate [ABR], 1.6; median spontaneous  ABR, 0.0)  –  Of these, 119 were spontaneous and 87 were traumatic bleeds (for 3 bleeds, the type of bleed is unknown)  – The location of bleeding episodes is shown in Figure 1A•   In the weekly prophylaxis group, 92 bleeding episodes were reported in 19 participants (median ABR, 3.59; median spontaneous ABR, 1.93)  – Of these, 60 were spontaneous and 32 were traumatic bleeds  – The location of bleeding episodes is shown in Figure 1BTreatment of Bleeding•   The majority of bleeding episodes were resolved with 1 or 2 rFVIIIFc infusions in the individualized prophylaxis and weekly prophylaxis groups (Figure 2) •   The median number of infusions of rFVIIIFc required to resolve a bleeding episode was 1.0 in both the individualized prophylaxis and weekly prophylaxis groups•   The median (IQR) dose per infusion required to resolve bleeding episodes was similar in both treatment groups (Figure 3)•   When evaluating their response to rFVIIIFc for the treatment of a bleeding episode, 78.8% and 64.8% of participants in the individualized prophylaxis and weekly prophylaxis groups, respectively, rated their response as either “excellent” or “good” (Figure 4) Safety •   rFVIIIFc was generally well tolerated and no serious vascular thrombotic events were reported•   No inhibitors were detected in any participant with an evaluable inhibitor testPopulation Pharmacokinetic Simulations of the Treatment of Bleeding  With rFVIIIFc•   Population pharmacokinetic simulations predicted that the majority of patients on prophylaxis who use rFVIIIFc to treat a bleeding episode in close proximity to their next scheduled prophylactic dose will have maximum factor activity levels that fall within the normal range (Figure 5) CONCLUSIONS•   Bleeding episodes among participants in the prophylaxis arms of the A-LONG study were rare •   rFVIIIFc was safe and effective when used to treat bleeding episodes in participants receiving routine prophylaxis, with most bleeds resolving with 1 or 2 rFVIIIFc infusions; efficacy for treatment of bleeding in the prophylaxis arms was consistent with that in the episodic treatment arm•   Clinical observations during A-LONG indicate that the maximal plasma factor activity level is reached immediately following infusion of rFVIIIFc.  Population pharmacokinetic simulations demonstrate that predicted maximum FVIII activity levels are likely to fall within the normal range for a majority of patients using rFVIIIFc prophylaxis when a bleeding event is treated in close proximity to a scheduled prophylaxis doseDisclosuresDQ: speakers bureaus for Baxter, Biogen, Grifols, and Novo Nordisk; advisory boards for Baxter, Bayer, and Octapharma.  JM: research funding from Bayer, Biogen, CSL Behring, and Novo Nordisk; advisory boards for Amgen, Bayer, Genentech, and Novo Nordisk.   AS: consultant for Baxter BioScience, Novo Nordisk, and LFB Biotechnologies.  JP: advisory boards for Bayer, BPL, Octapharma, Biogen, and Pfizer; educational support and travel grants from Octapharma, Pfizer, Biogen, and Novo Nordisk.  GFP: shareholder and former employee of Biogen Idec.  SL, ET, GA, and BR: employees of and equity interest in Biogen Idec.  This research was funded by Biogen Idec. AcknowledgmentsThe authors would like to acknowledge Sophie Zhu for her contributions to the abstract.  The development of this poster was supported by Biogen Idec (Cambridge, MA, USA).  Editorial assistance was provided by Melissa Yuan, MD, of MedErgy (Yardley, PA, USA), and was funded by Biogen Idec.References 1.  Manco-Johnson MJ, et al. N Engl J Med. 2007;357(6):535-544. 2. Fischer K, et al. Haemophilia. 2014;20(suppl 4):106-113. 3. Mahlangu J, et al. Blood. 2014;123(3):317-325. 4.  Nestorov I, et al. Clin Pharmacol Drug Dev. 2014. [Epub ahead of print] 5. Powell JS, et al. Blood. 2012;119(13):3031-3037. 6.  Shapiro AD, et al. J Thromb Haemost. 2014. [Epub ahead of print]Table 1.  Recommended rFVIIIFc Dosing by Bleeding Episode SeverityaBleeding episode severity rFVIIIFc doseMinor 10–20 IU/kgModerate to severe 15–30 IU/kgMajor to life threatening40–50 IU/kg initial dose followed by20–25 IU/kg every 12–24 hours until bleeding episode resolveda If a bleeding episode occurred or was ongoing at the time a prophylactic dose of rFVIIIFc was scheduled, the participant  was to treat the bleeding episode using a dose no less than his regular prophylaxis dose.Table 2.  Demographic and Baseline CharacteristicsIndividualized  prophylaxis group (n = 118)Weekly prophylaxis group (n = 24)Age, y, median (range) 29 (12–65) 31.5 (18–59)Weight, kg, median (range) 71.65 (42.0–127.4) 75.85 (50.0–105.0)Race, n (%)a   White   Black   Asian   Other79 (66.9)7 (5.9)27 (22.9)5 (4.2)12 (50.0)1 (4.2)11 (45.8)0Geographic location, n (%)   Europe   North America   Otherb34 (28.8)44 (37.3)40 (33.9)3 (12.5)5 (20.8)16 (66.7)Prestudy FVIII regimen, n (%)   Prophylaxis   Episodic treatment87 (73.7)31 (26.3)024 (100)Estimated bleeding events in prior  12 months, median (IQR)c   Prior prophylaxis   Prior episodic treatment6.0 (2–15)27 (17–41)−29.5 (19–44)1 or more target joint, n (%)   Prior prophylaxis   Prior episodic treatment47 (39.8)26 (22.0)−22 (91.7)aPercentages may not total 100.0% due to rounding. bOther included Australia, New Zealand, Brazil, Hong Kong, India, Japan, Russia, and South Africa.cCalculation was based on available data.0102030405060708090100Weeklyprophylaxis groupIndividualizedprophylaxis group85.696.7 96.780.4Resolved bleeding episodes (%)1–2 infusions1 infusionFigure 2.  Percentage of bleeding episodes resolved with 1 or 1–2 rFVIIIFc infusions. No responseto treatmentModerateExcellentor good1.320.078.831.3Excellent47.5Good15.7Excellent49.1Good0.934.364.8020406080100No responseto treatmentModerateExcellentor goodA.  Individualized prophylaxis group B.  Weekly prophylaxis groupPercentage of responsePercentage of responseParticipants’ assessment of responseParticipants’ assessment of response020406080100Figure 4.  Participants’ assessment of response to treatment for all infusions.a aRecorded within 8 to 12 hours of first infusion.0.1110010Time (d)75 100250 50 150 175 200125FVIII activity (IU/dL)0.1110010Time (d)Regular prophylaxis (50 IU/kg)75250 50 125 150100FVIII activity (IU/dL)Bleeding treatment (25 IU/kg)54.8(34.4, 91.9)116(74.1, 186)97.5thMedian75th25th2.5thMedian Cmax(IU/dL; 95% PI):62.6(37.3, 112)120(74.8, 196)97.5thMedian2.5th25th75thMedian Cmax(IU/dL; 95% PI):A.  rFVIIIFc 50 IU/kg every 4 days prophylaxis dosing regimenB.  rFVIIIFc 50 IU/kg every 3 days prophylaxis dosing regimenProphylaxis BleedingtreatmentProphylaxisProphylaxis BleedingtreatmentProphylaxisFigure 5.  Predicted FVIII activity versus time profiles when a bleeding episode is treated with rFVIIIFc (25 IU/kg, regardless of prophylaxis dosing regimen) 24 hours before a scheduled prophylactic dose.a,b  Cmax = maximum concentration; PI = prediction interval.a Based on the incremental recovery observed in A-LONG, a rFVIIIFc dose of 25 IU/kg is expected to increase factor activity  by approximately 50 IU/dL.b The median time to 1% with a single dose of rFVIIIFc 50 IU/kg is 4.9 days.3  At steady state, a prophylaxis regimen of rFVIIIFc 50 IU/kg every 3 days would be predicted to maintain 89.4% of individuals above 1%, and a prophylaxis regimen of rFVIIIFc 50 IU/kg every 4 days would be predicted to maintain 67.2% of individuals above 1%.6  67%16%11%5%1% 2%65%22%5%6%InternalSkin/mucosaSoft tissueMuscleJointsA.  Individualized prophylaxis group B.  Weekly prophylaxis groupFigure 1.  Bleeding episodes by location.aaA single bleeding episode could have been reported in ≥1 location.29.94 32.63 30.2621.65Weeklyprophylaxis groupIndividualizedprophylaxis groupMedian (IQR) dose (IU/kg)0102030405060Total doseDose per infusionFigure 3.  Median (IQR) dose per infusion and total dose (IU/kg) of rFVIIIFc required to resolve a bleeding episode.

Predicting FVIII Activity in Patients Who Use Recombinant FVIII Fc Fusion Protein for Prophylaxis and Treatment of Bleeding Episodes

https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/7668/PASI%20Predicting%20FVIII%20Activity%202014.pdf?sequence=3

Predicting FVIII Activity in Patients Who Use Recombinant FVIII Fc Fusion Protein for Prophylaxis and Treatment of Bleeding Episodes

Abstract

Similar works

Full text

Available Versions

Queen Mary Research Online