scholarly journals Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: Results from the phase 3 PROPEL study

Blood ◽  
2020 ◽  
Author(s):  
Robert Klamroth ◽  
Jerzy Windyga ◽  
Vlad Radulescu ◽  
Peter W Collins ◽  
Oleksandra Stasyshyn ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Severe Disease ◽  
Treatment Trial ◽  
Phase 3 ◽  
Bleeding Rate ◽  
Fviii Inhibitor ◽  
Point Estimates ◽  
Dosing Frequency ◽  
Full Analysis ◽  
Trough Levels

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% is efficacious and well-tolerated in people with hemophilia A (PwHA). As some may benefit from higher FVIII troughs, the PROPEL trial compared safety and efficacy of 2 target FVIII trough levels in PwHA with severe disease, aged 12-65 years, annualized bleeding rate ≥2, and previous FVIII treatment. They were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1-3% (reference arm) or 8-12% (elevated arm). Treatment-adjustment period was in the first 6 months. Primary endpoint: proportion of PwHA (full analysis set [FAS]) with zero total bleeds (all bleeds) during second 6 months. Overall, 115 male PwHA were randomized (N=115, FAS; N=95, per-protocol analysis set [PPAS]). In the 1-3% and 8-12% arms, respectively, point estimates (95% CI) of proportions of PwHA with zero total bleeds were 42% (29-55%) and 62% (49-75%) in FAS (P=0.055) and 40% (27-55%) and 67% (52-81%) in PPAS (P=0.015). Dosing frequency and consumption varied widely in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA. Serious AEs occurred in 7/115 (6%) PwHA, including 1 treatment-related serious AE in 8-12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms, with no new safety signal in the 8-12% arm vs previous studies. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and also emphasize the importance of personalized treatment. Trial registration: www.ClinicalTrials.gov (#NCT02585960).

Improved Clinical Outcomes and Replacement FVIII Consumption in Patients with Hemophilia a after Prophylaxis Adjustment Using a FVIII Pharmacokinetics Estimation Based on Bayesian Models

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3780-3780
Author(s):  
Maria Eva Mingot-Castellano ◽  
Rafael Parra ◽  
Ramiro Nuñez ◽  
Marta Martorell ◽  
Ana Isabel Heiniger Mazo
Keyword(s):  
Clinical Practice ◽  
Research Funding ◽  
Hemophilia A ◽  
Bayesian Models ◽  
Severe Bleeding ◽  
Bleeding Rate ◽  
Two Samples ◽  
Before And After ◽  
The Impact ◽  
Trough Levels

Abstract INTRODUCTION Current guidelines recommend that subjects with severe hemophilia A (HA) receive prophylaxis in order to prevent severe bleeding and recurrent hemarthrosis that lead to the development of arthropathy, an extremely painful and disabling condition. Success of this approach greatly depends on treatment individualization, and the pharmacokinetics (PK) of factor VIII (FVIII) replacement therapy in a given patient is a crucial consideration. Standard PK studies require extraction of 6 to 10 samples, a procedure that takes several hours and causes adult patients and the parents of pediatric patients to miss work and children to miss school. This represents a significant barrier for routine performance of PK tests, and more rapid methods are needed in order to universalize PK-based adjustment in clinical practice. Björkman et al. developed a method to estimate PK parameters of factor FVIII using Bayesian models (Haemophilia 2010, 16(4):597-605). This approach requires only 2-3 blood extractions between 4 and 48 h after infusion, and may help introduce PK-based tailoring in hemophilia clinics. Based on this methodology, an online tool was developed to perform PK estimates in patients using the FVIII product Advate® (myPKFiT®, www.mypkfit.com; Baxter Healthcare Corporation; Haemophilia 2014, 20 (Suppl.2):15). This report describes the impact of using this tool to adjust prophylaxis regimens in clinical practice, in terms of clinical bleeding and joint bleeding rates and FVIII consumption, in subjects with HA receiving prophylaxis. METHODS This is an observational case series of 3 Spanish centers. Thirty-four patients were evaluated (30 severe and 4 moderate HA) aged 7-52 years (median 22 years). All were receiving prophylaxis, and all received Advate® as replacement factor. myPKFiT® was used for estimations in 2014-2015. FVIII trough levels were adjusted between 1% and 2%. We evaluated the annual bleeding rate (ABR), the annual joint bleeding rate (AJBR) and annual FVIII use before and after PK adjustment of prophylaxis using the study tool. RESULTS Of the 34 patients,16 had not previously undergone a PK study (NPAP group), while 18 had already had their therapy previously adjusted by trough FVIII levels determination (PAP group). Most patients (n = 23) were following an M/W/F infusion schedule before myPKFiT® study. Median weight was 60 kg (interquartile range [IQR] = 32-78). Two samples were used for determinations in 27 patients, 3 in 5, and 4 in 2. Median FVIII half-life calculated with the study tool was 11.95 h (IQR = 10.13-14.33); median clearance was 0.035 dl/h/kg (IQR = 0.027-0.042), and median time until FVIII level 1% was 59.5 (IQR = 50.8-72.0). FVIII use, ABR and ABJR before and after adjustment with the parameters provided by myPKFiT® are summarized in Table 1. Adjustment had an impact in the individual factor consumption of most patients: in 14 cases, the annual amount was reduced (mean −34824 ± 49925 IU/year), and in 16 it was increased (mean +60605 ± 43517 IU/year). However, this did not have a significant impact in the mean amount used in the whole series compared to that used the year prior to myPKFiT-adjusted prophylaxis (p = 0.196). Regarding clinical outcome, ABR and AJBR were both significantly reduced in the NPAP group, where 68.7% and 62.5% of patients reduced their ABR (p = 0.008) and AJBR (p = 0.008), respectively, after adjustment. These rates were generally maintained after myPKFiT-based personalization in the PAP group. CONCLUSIONS Clinical experience in this series suggests that PK-adjusted prophylaxis by means of a tool such as myPKFiT® may have a favorable impact on the prophylaxis regimens of HA patients. Clinical benefit can be achieved in patients whose therapy has not previously been adjusted using PK-based methods, and this personalized approach can reduce bleeding rates without significantly increasing the overall cost of FVIII therapy. Furthermore, the maintenance of bleeding rates in patients with prophylaxis previously adjusted by determination of trough levels suggests that outcomes with this method might be comparable. Disclosures Mingot-Castellano: Amgen: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding; Novartis: Consultancy; Bayer: Consultancy, Research Funding. Parra:Baxalta: Consultancy.

scholarly journals Effectiveness of Monthly Low-Dose Emicizumab Prophylaxis without 4-Week Loading Doses Among Patients with Hemophilia a with and without Inhibitor: A Case Series Report

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2116-2116
Author(s):  
Ampaiwan Chuansumrit ◽  
Nongnuch Sirachainan ◽  
Suphaneewan Jaovisidha ◽  
Tachit Jiravichitchai ◽  
Praguywan Kadegasem ◽  
...  
Keyword(s):  
Vitamin D ◽  
Factor Viii ◽  
Low Dose ◽  
Hemophilia A ◽  
Bleeding Risk ◽  
Z Score ◽  
Bleeding Rate ◽  
Effective Prophylaxis ◽  
Trough Levels

Abstract Introduction: Emicizumab is a humanized, bispecific, monoclonal antibody proven as an effective prophylaxis for patients with hemophilia A with and without inhibitor. After the weekly loading of 3 mg/kg for 4 doses followed by maintenance dose of 1.5 to 6 mg/kg at 1 to 4-week intervals, the equivalent factor VIII was maintained at approximately 15% and showed an effective prophylaxis in reducing annual bleeding rate. Due to the health care resource constraint, the dose of emicizumab was reduced to maintain the prophylaxis factor VIII at 1-3%. Methods: The effectiveness of monthly low dose emicizumab prophylaxis without 4 loading doses was evaluated among patients with hemophilia A with and without inhibitor for at least 6 months. The bone mineral density (BMD), ultrasonography of bilateral ankle, elbow and knee as well as Hemophilia Joint Health Score (HJHS) were initially evaluated and planned to be repeated after one year treatment. The vitamin D level was determined initially, and vitamin D supplement was prescribed for 3 patients with low vitamin D levels at 13.3, 23.2 and 24.6 ng/mL. Moreover, the quality of life assessment using Hemo-QoL and CHO-KLAT was performed in 3-month intervals. Results: Five patients without inhibitor (3 severe, 2 moderate) and 1 patient with severe hemophilia A with inhibitor enrolled in the study. They all behaved in low bleeding risk circumstances such as avoidance of contact sport. Their ages ranged from 4 to 40 years of age. The youngest boy had difficulty at peripheral venous access for regular prophylaxis while the remaining 4 patients without inhibitor experienced frequent breakthrough bleeding episodes while receiving a low dose prophylaxis at 500 to 1,000 units of factor VIII concentrate twice weekly. All refused to receive more frequent prophylaxis. For patient with inhibitor, the high inhibitor titer of 65 Bethesda units (BU) declined during the 2 years of immune tolerance induction (ITI) at the intermediate dose of 100 units/kg of extended half-life factor VIII concentrate 3 times weekly. His lowest inhibitor was at 10 BU and was documented as failed ITI. He experienced frequent bleeding at the muscles and joints for which bypassing agents could not be adequately provided. For the baseline study, 2 patients had low BMD Z score ≤-2.0 while the remaining 4 patients had normalized BMD Z score >-2.0. The ultrasonography of bilateral ankle, elbow and knee at anterior, medial, lateral and posterior/inferior spaces revealed joint distension reflecting varying-degree synovial hypertrophy and/or bleeding component of 0-14.0, 0-9.8, 0-9.4, 0-12.8; 0-14.4, 0-17.8, 0-10.7, 0-18.6 and 0-23.8, 0-15.3, 0-17.1, 0-12.9 millimeter, respectively. Varying-degree hyperemia from the ultrasonography reflecting active inflammation of synovium was found in 4 ankles, 6 elbows and 4 knees of the total 36 joints in 4 of 6 patients. The HJHS scores ranged from 6 in the youngest patient to 56 in the patient with inhibitor. All patients except the 4-year-old boy had 1 to 3 target joints. All the studied patients received 1 each of the whole vial of emicizumab at 30, 75, 105 mg monthly except 3 patients receiving 60 mg monthly which was equal to 1.1 to 1.6 mg/kg of emicizumab. The monthly trough levels of emicizumab determined by a modified one stage factor VIII assay using emicizumab calibrator were maintained at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3% (0.3% FVIII per µg/ml of emicizumab). The bleeding rate was markedly decreased from 4-8 episodes monthly to 0-1 episode monthly. The monthly zero bleeding rate was found among 4 patients. Moreover, the swollen target joint gradually dissolved. Their quality of life markedly improved evaluated by the Hemo-QoL and CHO-KLAT. They could attend regular school and work happily. The HJHS and ultrasonography have not been repeated yet. Conclusion: The monthly low dose emicizumab prophylaxis of the whole vial at 1.1 to 1.6 mg/kg without loading dose could achieve emicizumab trough levels at 3.8 to 9.8 µg/ml which were equivalent to the levels of FVIII at 1 to 3%. It showed effective prophylaxis among patients with hemophilia with and without inhibitor who performed low bleeding risk activity. The 3 aspects of body functions and structures, activities and participation were gradually improved. Disclosures No relevant conflicts of interest to declare.

A Multicenter Pharmacosurveillance Study for the Evaluation of the Efficacy and Safety of Recombinant Factor VIII in the Treatment of Patients with Hemophilia A

1997 ◽  
Vol 78 (05) ◽  
pp. 1352-1356 ◽  
Author(s):  
Emel Aygören-Pürsün ◽  
Inge Scharrer ◽  
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Parvovirus B19 ◽  
Subjective Evaluation ◽  
Recombinant Factor Viii ◽  
Fviii Inhibitor ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Bleeding Episodes ◽  
Recombinant Fviii

SummaryIn this open multicenter study the safety and efficacy of recombinant factor VIII (rFVIII) was assessed in 39 previously treated patients with hemophilia A (factor VIII basal activity ≤15%).Recombinant FVIII was administered for prophylaxis and treatment of bleeding episodes and for surgical procedures. A total of 3679 infusions of rFVIII were given. Efficacy of rFVIII as assessed by subjective evaluation of response to infusion and mean annual consumption of rFVIII was comparable to that of plasma derived FVIII concentrates. The incremental recovery of FVIII (2.4 ± 0,83%/IU/kg, 2.12 ± 0.61%/IU/kg, resp.) was within the expected range. No clinical significant FVIII inhibitor was detected in this trial. Five of 16 susceptible patients showed a seroconversion for parvovirus B19. However, the results are ambiguous in two cases and might be explained otherwise in one further case. Thus, in two patients a reliable seroconversion for parvovirus B19 was observed.

scholarly journals Factor VIII Use in the Treatment of Breakthrough Bleeds in Hemophilia A Patients without Inhibitors on Emicizumab Prophylaxis: The Phase 3 HAVEN 3 Study Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2395-2395
Author(s):  
Michael Callaghan ◽  
Benjamin Trzaskoma ◽  
Richard H. Ko ◽  
Lucy Lee ◽  
Anisha M. Patel ◽  
...  
Keyword(s):  
Factor Viii ◽  
Exposure Time ◽  
Cumulative Dose ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 3 ◽  
Breakthrough Bleeding ◽  
On Demand ◽  
Equity Ownership ◽  
The Individual

Introduction HAVEN 3 was a phase 3 study investigating the use of emicizumab as prophylaxis in adult and adolescent (≥12 years old) persons with hemophilia A (PwHA) without factor VIII (FVIII) inhibitors (NCT02847637; Mahlangu et al. 2018). HAVEN 3 demonstrated that emicizumab prophylaxis once weekly or every two weeks was safe and highly effective in bleed prevention. The primary analysis of HAVEN 3 included an intrapatient comparison of 48 participants who received FVIII prophylaxis in a non-interventional study (NIS) prior to enrollment in HAVEN 3. Compared with emicizumab prophylaxis during the HAVEN 3 study, emicizumab prophylaxis resulted in an annualized bleed rate that was 68% lower than the rate with previous FVIII prophylaxis (1.5 vs 4.8, p<0.001). No dosing guidance was provided regarding the use of on-demand FVIII in HAVEN 3, and investigators prescribed FVIII at their own discretion. In this subsequent analysis, we characterize the dose and frequency of replacement FVIII used for the treatment of breakthrough bleeding in these 48 participants. Methods The primary comparisons in our analyses are focused on on-demand FVIII use for breakthrough bleeding while participants were on FVIII prophylaxis during the NIS versus its use while on emicizumab prophylaxis during HAVEN 3. Any use of on demand FVIII other than to manage breakthrough bleeding (e.g. prior to activity) was not included in our analyses. Given that, collectively, the total exposure time to emicizumab during HAVEN 3 was more than twice the exposure time to FVIII prophylaxis during the NIS (75.8 vs 28.6 years respectively), any treatment comparisons are drawn on an annualized basis. Annualized on-demand FVIII use was calculated by dividing by the number of days in the efficacy period and multiplying the resulting daily consumption by 365.25 days. The number of infusions and cumulative doses of on-demand FVIII use are described at the participant level as well as at the individual bleed level and are presented descriptively for both the NIS and HAVEN 3 exposure periods. No formal statistical inferences (i.e. calculation of p-values) have been conducted. All analyses were based on an October 2018 data cutoff. Results A total of 48 participants who were treated with FVIII prophylaxis during the NIS were then treated with emicizumab prophylaxis during HAVEN 3 and thus make up the total cohort for our analyses. Annualized infusion rates of on-demand FVIII per participant and cumulative doses of on-demand FVIII (in international units [IU] per kilogram) per participant were higher during the FVIII prophylaxis period when compared with the emicizumab exposure period (mean 15.3 vs 7.2; median 3.6 vs 0.6 annual infusions per participant and mean 602.4 IU/kg vs 209.0 IU/kg; median 75.5 IU/kg vs 19.1 IU/kg, respectively). At the individual bleed level, FVIII infusions and total cumulative dose suggested that participants were administered a similar amount of medication to treat bleeds during both the NIS and HAVEN 3 study periods: median number of infusions per bleed were 1.0 (interquartile range [IQR]=1.0) versus 2.0 (IQR=3.0) and median cumulative doses were 43.5 (IQR=35.1) versus 50.0 (IQR=72.7) IU/kg, respectively (Table 1). Conclusions This analysis revealed a lower annualized infusion rate and a correspondingly lower annualized cumulative dose of FVIII for treatment of breakthrough bleeds during emicizumab prophylaxis compared with FVIII prophylaxis. At the individual bleed level, the amount of on-demand FVIII used per bleeding episode was comparable between NIS and HAVEN 3 exposure periods. Thus, based on this single analysis, it appears that patients received less on-demand FVIII during emicizumab prophylaxis compared with FVIII prophylaxis, as a result of overall reduction of bleed frequency, while the treatment of individual bleeds appeared similar regardless of the prophylaxis therapy administered. Disclosures Callaghan: Octapharma: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Bayer: Consultancy, Speakers Bureau; Alnylum: Equity Ownership; Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Roche/Genentech: Speakers Bureau; Shire/Takeda: Speakers Bureau; Pfizer: Research Funding; Roche: Research Funding. Trzaskoma:Genentech: Employment, Equity Ownership. Ko:Genentech, Inc.: Employment. Lee:Genentech, Inc.: Employment. Patel:Genentech: Employment; Roche/Genentech: Equity Ownership. Tzeng:Genentech, Inc.: Employment. Shah:Genentech: Employment. Chang:Genentech, Inc.: Employment; Genentech/Roche: Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Dhalluin:F. Hoffmann-La Roche Ltd: Employment. Mahlangu:Sanofi: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Biomarin: Research Funding; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; Unique: Research Funding.

scholarly journals Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262273
Author(s):  
Carolina J. Delgado-Flores ◽  
David García-Gomero ◽  
Stefany Salvador-Salvador ◽  
José Montes-Alvis ◽  
Celina Herrera-Cunti ◽  
...  
Keyword(s):  
Low Dose ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Clotting Factor ◽  
High Dose ◽  
Bleeding Rate ◽  
Episodic Treatment ◽  
Grade Methodology ◽  
Inform Decision Making ◽  
Intermediate Dose

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

scholarly journals A Population Pharmacokinetic Model for Concizumab Based on Phase 1 and Phase 2 Trial Data

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Trine Høyer Rose ◽  
Christian Hollensen ◽  
Henrik Agersø ◽  
Rune Viig Overgaard
Keyword(s):  
Rate Constant ◽  
Drug Disposition ◽  
Hemophilia A ◽  
Phase 1 ◽  
Population Pharmacokinetic ◽  
Phase 2 ◽  
Publicly Traded ◽  
Phase 3 ◽  
Target Mediated Drug Disposition ◽  
Population Pk

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure

2020 ◽  
Vol 221 (11) ◽  
pp. 1752-1756 ◽  
Author(s):  
Nir Eyal ◽  
Marc Lipsitch ◽  
Peter G Smith
Keyword(s):  
Natural Infection ◽  
Severe Disease ◽  
Baseline Risk ◽  
Phase 3 ◽  
Live Virus ◽  
Mortality And Morbidity ◽  
Vaccine Candidates ◽  
Frequent Monitoring ◽  
Serious Disease ◽  
Related Mortality

Abstract Controlled human challenge trials of SARS-CoV-2 vaccine candidates could accelerate the testing and potential rollout of efficacious vaccines. By replacing conventional phase 3 testing of vaccine candidates, such trials may subtract many months from the licensure process, making efficacious vaccines available more quickly. Obviously, challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity. Volunteers in such studies could autonomously authorize the risks to themselves, and their net risk could be acceptable if participants comprise healthy young adults, who are at relatively low risk of serious disease following natural infection, if they have a high baseline risk of natural infection, and if during the trial they receive frequent monitoring and, following any infection, the best available care.

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