scholarly journals Efanesoctocog alfa for hemophilia A: results from a phase 1 repeat-dose study

2021 ◽  
Author(s):  
Toshko Jelev Lissitchkov ◽  
Annemieke Willemze ◽  
Suresh Katragadda ◽  
Kara Rice ◽  
Stacey Poloskey ◽  
...  
Keyword(s):  
Half Life ◽  
Hemophilia A ◽  
Phase 1 ◽  
Geometric Mean ◽  
Repeat Dose ◽  
Post Dose ◽  
Time Curve ◽  
Safety Concerns ◽  
Fviii Activity ◽  
Dose Study

Efanesoctocog alfa (rFVIIIFc-VWF-XTEN, BIVV001) is a new class of factor VIII (FVIII) replacement that breaks the von Willebrand factor-imposed FVIII half-life ceiling. In a Phase 1/2a study, single-dose efanesoctocog alfa was well tolerated and no safety concerns were identified. We evaluated the safety, tolerability, and pharmacokinetics of repeat-dose efanesoctocog alfa in a Phase 1 study in previously treated adults (≥150 exposure days) with severe hemophilia A. Participants received four once-weekly efanesoctocog alfa doses (Cohort 1, 50 IU/kg; Cohort 2, 65 IU/kg). All enrolled participants (Cohort 1, n=10; Cohort 2, n=14) completed the study. Inhibitor development to FVIII was not detected. After the last efanesoctocog alfa dose, geometric mean (range) FVIII activity half-life, area under the activity-time curve, and steady state maximum concentration for Cohort 1 and Cohort 2 were 41.3 (34.2-50.1) hours and 37.3 (28.9-43.8) hours, 8290 (5810-10,300) h × IU/dL and 11,200 (7040-15,800) h × IU/dL, and 131 (96-191) IU/dL and 171 (118-211) IU/dL, respectively. There was minimal accumulation after 4 doses. Mean FVIII activity on Day 3 post dose was 46% and 69% and on Day 7 was 10% and 12% for Cohorts 1 and 2, respectively. Overall, four once-weekly doses of efanesoctocog alfa were well tolerated, no safety concerns identified, and no bleeds reported during the treatment period. Once-weekly efanesoctocog alfa provided high sustained FVIII activity within the normal to near-normal range for 3-4 days post-dose and may improve protection against bleeds in patients with hemophilia A. (EU Clinical Trials Register study 2018-001535-51)

scholarly journals Phase 1 Repeat Dosing with BIVV001: The First Investigational Factor VIII Product to Break through the Von Willebrand Factor-Imposed Half-Life Ceiling

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 625-625 ◽  
Author(s):  
Toshko Lissitchkov ◽  
Kara Rice ◽  
Suresh Katragadda ◽  
Annemieke Willemze ◽  
Craig Benson ◽  
...  
Keyword(s):  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 1 ◽  
Geometric Mean ◽  
Activity Levels ◽  
Severe Hemophilia ◽  
Fviii Activity ◽  
Equity Ownership ◽  
Von Willebrand

Introduction The use of factor VIII (FVIII) replacement products enables comprehensive management (prophylaxis, acute bleed control, and perioperative hemostasis) of patients with severe hemophilia A. Prophylaxis with standard half-life FVIII replacement therapies requires frequent administration, and low FVIII activity levels between infusions lead to an increased risk of bleeds. FVIII replacement products that achieve optimal bleed protection with once-weekly dosing intervals remain an unmet need for people living with severe hemophilia A. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel FVIII therapy composed of single-chain FVIII, the Fc domain of human immunoglobulin G1, the FVIII-binding D′D3 domain of von Willebrand factor (VWF), and 2 XTEN polypeptides. BIVV001 is designed to be a next-generation FVIII therapy that circulates independently of endogenous VWF, thereby breaking the VWF-imposed half-life ceiling. Single-dose BIVV001 was well tolerated and provided sustained FVIII activity in a first-in-human trial (Konkle et al, Blood, 2018). Here, we report final data for an open-label Phase 1 trial to assess the safety, tolerability, and pharmacokinetics (PK) of repeat dosing with BIVV001 in subjects with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII) (EudraCT No: 2018-001535-51). Methods Eligible subjects were 18-65 years of age, had severe hemophilia A, and ≥150 exposure days to prior FVIII products. After screening and washout, subjects received 4 once-weekly doses of BIVV001 (Days 1, 8, 15, and 22) at either 50 IU/kg (Cohort 1) or 65 IU/kg (Cohort 2). The safety observation period extended for 28 days after the last dose of BIVV001. Primary endpoints were the occurrence of adverse events and clinically significant abnormalities in laboratory tests, including inhibitor development. Secondary endpoints were PK parameters derived from FVIII activity evaluated using a one-stage activated partial thromboplastin time clotting assay. PK blood samples were collected immediately before BIVV001 infusion on Days 1, 8, 15, and 22 and at multiple times after dosing on Days 1 and 22. Results All subjects enrolled in Cohort 1 (n=10) and Cohort 2 (n=14) completed the study. Mean (range) age of subjects was 35 (25-55) years for Cohort 1 and 41 (24-58) years for Cohort 2. BIVV001 was well tolerated. No inhibitor development to FVIII was detected, and there were no events of hypersensitivity or anaphylaxis reported. Baseline-corrected PK data were available for 9 subjects in Cohort 1 and all subjects in Cohort 2. Consistent with the single-dose study, the geometric mean (range) half-life for 50 IU/kg and 65 IU/kg BIVV001 was 41.3 (34.2-50.1) hours and 37.3 (28.9-43.8) hours, respectively. After 4 weekly doses of BIVV001 (Day 22), geometric mean (range) area under the activity-time curve from hour 0 over the dosing interval (AUC0-tau) and maximum concentration at steady state (Cmaxss) of BIVV001 were 8290 (5810-10,300) hr × IU/dL and 131 (96-191) IU/dL for Cohort 1 and 11,200 (7040-15,800) hr × IU/dL and 171 (118-211) IU/dL for Cohort 2, respectively. Mean (standard deviation) FVIII activity immediately prior to the final dose of BIVV001 (Ctrough) was 9.9 (2.8) IU/dL in Cohort 1 and 11.7 (5.5) IU/dL in Cohort 2. The mean (range) Day 22-Day 1 accumulation index was 1.07 (1.03-1.11) for Cohort 1 and 1.05 (1.02-1.08) for Cohort 2. At 5 and 7 days after the final BIVV001 infusion, mean steady-state FVIII activity was 22% and 10% for Cohort 1 and 27% and 12% for Cohort 2, respectively (Figure). Geometric mean (range) incremental recovery after the first dose of BIVV001 was 2.3 (1.6-2.8) IU/dL per IU/kg for Cohort 1 and 2.4 (1.6-3.3) IU/dL per IU/kg for Cohort 2. Conclusions Four weekly infusions of 50 IU/kg or 65 IU/kg BIVV001 were well tolerated with no identified safety concerns. FVIII activity levels were sustained and nonaccumulating between doses. By breaking through the VWF-imposed half-life ceiling, BIVV001 prophylaxis may lead to more optimal, extended protection against bleeds for patients with severe hemophilia A than standard FVIII therapies. These results support the continued development of BIVV001 in a Phase 3 clinical trial program. Disclosures Lissitchkov: Roche: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Sanofi: Equity Ownership, Research Funding; Bayer: Consultancy, Equity Ownership, Honoraria, Other: Principal investigator for clinical trials, Research Funding; Sobi: Consultancy, Equity Ownership, Honoraria; Shire: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Octapharma: Equity Ownership, Research Funding. Rice:Sanofi: Employment. Katragadda:Sanofi: Employment. Willemze:Sanofi: Employment. Benson:Sanofi: Employment. Knobe:Sanofi: Employment.

scholarly journals 633. Preliminary Results from a Phase 1 Single Ascending-Dose Study Assessing Safety, Serum Viral Neutralizing Antibody Titers (sVNA), and Pharmacokinetic (PK) Profile of ADG20: an Extended Half-Life Monoclonal Antibody Being Developed for the Treatment and Prevention of Coronavirus Disease (COVID-19)

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S420-S420
Author(s):  
Helen Paguntalan ◽  
Zoltán Magyarics ◽  
Lynn E Connolly ◽  
Ellie Hershberger ◽  
Kristin Narayan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Half Life ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Post Dose ◽  
Treatment And Prevention ◽  
Dose Study ◽  
Antibody Titers ◽  
Single Ascending Dose Study ◽  
Ongoing Phase

Abstract Background ADG20 is a fully human IgG1 monoclonal antibody engineered to have high potency and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential by binding to a highly conserved epitope in the receptor-binding domain (RBD) of the spike protein. The Fc region of ADG20 has been modified to provide an extended half-life. ADG20 is in clinical development for the treatment and prevention of COVID-19. Methods This is an ongoing Phase 1, randomized, placebo (PBO)-controlled, single ascending-dose study of ADG20 administered intramuscularly (IM) or intravenously (IV) to healthy adults aged 18–50 years with no evidence of prior or current SARS-CoV-2 infection. Participants were randomized 8:2 in 3 cohorts (N=10/cohort: n=8 ADG20, n=2 PBO): ADG20 300 mg IM, 500 mg IV, and 600 mg IM. Safety, tolerability, PK, and sVNA titers were assessed up to 3 months post dose. Serum ADG20 concentrations were measured with a validated hybrid ligand binding liquid chromatography–mass spectrometry (MS)/MS assay. sVNA titers against authentic SARS-CoV-2 were determined by a plaque reduction neutralization assay. Results Overall, 30 participants received ADG20 (n=24) or PBO (n=6). Blinded safety data for all cohorts and PK/sVNA titer data for the 300 mg IM cohort are reported. Through a minimum of 10 weeks post dose, no study drug-related adverse events (AEs), serious AEs, injection site reactions, or hypersensitivity reactions were reported. The observed preliminary PK profile was dose proportional, consistent with an extended half-life monoclonal antibody, and well predicted by translational physiologically-based PK modeling. The measured 50% sVNA titer (MN50; geometric mean [coefficient of variation, %]) was 1382 (32.7%) 13 days after a single 300 mg IM dose. These values are within the range of peak serum neutralizing antibody titers reported for COVID-19 mRNA vaccines. Conclusion A single dose of ADG20, up to 600 mg IM, was well tolerated. Preliminary PK and sVNA titer profiles support the ongoing Phase 2/3 trials of ADG20 at a 300 mg IM dose for the prevention of COVID-19 (EVADE: NCT04859517) and treatment of ambulatory patients with mild to moderate COVID-19 (STAMP: NCT04805671). Disclosures Helen Paguntalan, MD, Adagio Therapeutics, Inc. (Scientific Research Study Investigator) Zoltán Magyarics, MD, PhD, Adagio Therapeutics, Inc. (Consultant) Lynn E. Connolly, MD, PhD, Adagio Therapeutics, Inc. (Employee) Ellie Hershberger, PharmD, Adagio Therapeutics, Inc. (Employee) Kristin Narayan, PhD, Adagio Therapeutics, Inc. (Employee) Deepali Gupta, BS, Adagio Therapeutics, Inc. (Employee) Paul G. Ambrose, PharmD, Adagio Therapeutics, Inc. (Employee) Frank Engler, PhD, Adagio Therapeutics, Inc. (Independent Contractor) Ed Campanaro, BSN, MSHS, Adagio Therapeutics, Inc. (Employee) Anita F. Das, PhD, Adagio Therapeutics, Inc. (Consultant) Pete Schmidt, MD, Adagio Therapeutics, Inc. (Employee)

scholarly journals 1371. Safety, Tolerability, and Pharmacokinetics of Multiple Doses of TP-6076, a Novel, Fully Synthetic Tetracycline, in a Phase 1 Study

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S420-S420 ◽  
Author(s):  
Larry Tsai ◽  
Alison Moore
Keyword(s):  
Physical Examination ◽  
Bacterial Infections ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Geometric Mean ◽  
Vital Signs ◽  
Gastrointestinal Adverse Event ◽  
Double Blind ◽  
Dose Study

Abstract Background TP-6076 is a novel, fully synthetic tetracycline being developed for the treatment of serious bacterial infections, including those caused by multidrug-resistant Acinetobacter baumannii. TP-6076 has demonstrated potent activity in vitro against carbapenem-resistant strains of A. baumannii, with MIC90 64 times lower compared with tigecycline and 256 times lower compared with minocycline. We now report the results of a multiple ascending dose study in normal healthy volunteers. Methods This was a phase 1, single-site, randomized, double-blind, placebo-controlled dose-escalating, multiple dose study in healthy adults who met the inclusion/exclusion criteria and provided informed consent prior to any study procedure. Cohorts of eight subjects each (six active and two placebo) received daily doses of 6.0 to 40.0 mg TP-6076 or placebo for 7 days. Plasma and urine samples for pharmacokinetic (PK) analyses were collected starting immediately prior to dosing until 96 hours after the last dose. Safety was assessed through collection of adverse events (AEs), clinical laboratories, vital signs, ECG, and physical examination data. Results The geometric mean derived PK parameters for TP-6076 were: There were no serious or severe AEs reported. The most frequently reported AEs were gastrointestinal events, including nausea and vomiting, and localized infusion site reactions. There were no clinically significant changes in clinical laboratory values, ECG parameters, or physical examination findings. Conclusion Following multiple IV doses of TP-6076, plasma exposure increased as dose increased. Multiple IV doses of TP-6076 were generally well tolerated, with higher gastrointestinal adverse event rates in the higher dose groups. Disclosures L. Tsai, Tetraphase Pharmaceuticals: Employee and Shareholder, Salary. A. Moore, Tetraphase Pharmaceuticals: Employee, Salary.

scholarly journals 1335. Safety and Pharmacokinetic Profile of PC786, a Novel Inhibitor of Respiratory Syncytial Virus L-protein Polymerase, in a Single and Multiple-Ascending Dose Study in Healthy Volunteer and Mild Asthmatics

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S407-S408
Author(s):  
Lindsey Cass ◽  
Amanda Davis ◽  
Alison Murray ◽  
Kathy Woodward ◽  
Kazuhiro Ito ◽  
...  
Keyword(s):  
Half Life ◽  
Board Member ◽  
Phase 1 ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Preclinical Studies ◽  
Laboratory Findings ◽  
L Protein ◽  
Syncytial Virus

Abstract Background RSV is the most common cause of bronchiolitis in infants and is responsible for severe respiratory infections in the elderly and immunocompromised populations. RSV replicates in the columnar epithelial cells of the proximal and distal airways which are accessible to inhaled therapies. PC786 is a potent non-nucleoside RSV L-protein polymerase inhibitor designed for inhaled delivery. In preclinical studies, PC786 exhibits prolonged lung tissue residence with minimal systemic exposure, thus limiting the potential for adverse systemic effects. Methods A phase 1 study was conducted to evaluate the safety and pharmacokinetics of PC786 delivered in a suspension formulation by nebulizer (PARI LC SPRINT® device). Healthy volunteers (HVs) received placebo or PC786 as single ascending doses (0.5–20 mg, Cohort (C) 1), 5 mg BD for 7 days (C2), or 10 mg BD for 7 days (C3). Mild asthmatics received a single dose of PC786 5 mg or placebo (C4). PC786 PK was measured in plasma and in nasal mucosal lining fluid (MLF) collected using a synthetic absorptive matrix. Results PC786 was well tolerated, with no significant adverse clinical nor laboratory findings. Following single inhaled doses PC786 appeared rapidly in the plasma; mean plasma Cmax of 190, 571, 1,760, and 3,270 pg/mL, for the 0.5, 2, 8, and 20 mg doses, respectively, were measured on average at 0.68 to 0.93 hours (Tmax) post-inhalation. Following administration of 5 mg BD (C2) the extent of accumulation was approximately 2-fold. The geometric mean apparent terminal half-life measured following 10 mg BD (C3) was 97 hours. The ratio of MLF:plasma concentrations ranged from 6,347 (+2 hours) to 1,050 (+24h). Conclusion PC786 was well tolerated by HVs and asthmatics. The compound showed a rapid Tmax, suggesting rapid exposure of the respiratory epithelium. The PC786 concentrations in MLF exceed the IC90 for RSV, but circulating plasma concentrations were low. The MLF:plasma measured in this study was consistent with lung:plasma ratios measured in preclinical studies. The long plasma half-life is consistent with slow absorption from the lung being the dominant process controlling systemic kinetic behavior. The long t½ and 2-fold accumulation ratio observed on repeat dosing supports once daily dosing in subsequent studies. Disclosures L. Cass, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Davis, Pulmocide Ltd.: Employee and Shareholder, Salary. A. Murray, Pulmocide Ltd.: Employee and Shareholder, Salary. K. Woodward, Pulmocide Ltd.: Consultant, Consulting fee. K. Ito, Pulmocide Ltd.: Employee and Shareholder, Salary. P. Strong, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary. G. Rapeport, Pulmocide Ltd.: Board Member, Employee and Shareholder, Salary.

Bleeding Phenotype with Various Bay 94-9027 Dosing Regimens: Subanalyses from the Protect VIII Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1526-1526 ◽  
Author(s):  
Lisa N. Boggio ◽  
Walter Hong ◽  
Maria Wang ◽  
M. Elaine Eyster ◽  
Lisa A. Michaels
Keyword(s):  
Half Life ◽  
Hemophilia A ◽  
Phase 1 ◽  
P Value ◽  
Phase 2 ◽  
Dosing Regimen ◽  
On Demand ◽  
Dosing Regimens ◽  
Previously Treated ◽  
Dosing Intervals

Abstract Introduction: Factor VIII (FVIII) products with a longer half-life may allow for longer intervals between treatments for patients with hemophilia A and may facilitate prophylaxis tailored to an individual’s bleeding phenotype. BAY 94-9027, a PEGylated FVIII product, demonstrated an extended half-life in a phase 1 trial and was well tolerated and efficacious in a phase 2/3 study with dosing intervals up to every 7 days. In this subanalysis of the phase 2/3 trial, bleeding frequency calculated based on the BAY 94-9027 prophylactic dosing regimen during the study was compared with reported bleeding frequency in the 12 months before enrollment. Also, on-study annualized bleeding rates (ABRs) for joint, spontaneous, and trauma bleeds are presented by treatment group. Methods: PROTECT VIII was a multinational, partially randomized, open-label, 36-week study in previously treated patients aged 12–65 years with severe hemophilia A and no history of FVIII inhibitors. Patients received BAY 94-9027 for 36 weeks either on demand or prophylactically. Patients were assigned to 1 of 3 prophylaxis dosing regimens based on the number of bleeds observed during a 10-week run-in period, during which all patients in the prophylaxis arm were treated with 25 IU/kg BAY 94-9027 2x/week. Patients with ≤1 breakthrough bleed during the 10-week period were randomized 1:1 to BAY 94-9027 45–60 IU/kg every 5 days or 60 IU/kg every 7 days. Patients with ≥2 breakthrough bleeds received 30–40 IU/kg BAY 94-9027 2x/week. ABR and annualized joint bleeding rate (AJBR) for the 12 months before the study (collected retrospectively at screening) were compared with values calculated in patients previously treated with prophylaxis who used BAY 94-9027 prophylaxis during the study (weeks 0–36 for the combined prophylaxis groups [including the 10-week period]; weeks 10–36 for the 3 assigned prophylaxis dosing regimens). ABRs for joint, spontaneous, and trauma bleeds during the study were analyzed for the on-demand and combined prophylaxis groups (weeks 0–36) and in relation to patients’ BAY 94-9027 dosing regimen (weeks 10–36). Results: The intent-to-treat population comprised132 patients (prophylaxis, n=112; on demand, n=20). In patients previously treated with prophylaxis, median ABR and AJBR during BAY 94-9027 prophylaxis (weeks 0–36) were lower than corresponding prestudy values; ABR and AJBR during weeks 10–36 for every-5-day, every-7-day, and 2x/week BAY 94-9027 dosing were also lower than or comparable to prestudy values (Table). Median ABRs for joint, spontaneous, and trauma bleeds were lower for the combined prophylaxis groups (weeks 0–36) compared with the on-demand group (combined prophylaxis groups: 1.5, 1.4, and 0.0, respectively; on-demand group: 16.3, 14.3, and 9.1). In the prophylaxis arms (weeks 10–36), median ABRs for joint, spontaneous, and trauma bleeds were 2.1, 0.0, and 0.0 for 2x/week dosing; 1.9, 0.0, and 0.0 for every-5-day dosing; and 1.9, 1.9, and 0.0 for every-7-day dosing. Abstract 1526. Table. Bleeding Frequency During BAY 94-9027 Prophylaxis vs Prestudy Values Combined Prophylaxis, 2x/week, week 10–36 Every 5 Days, Every 7 Days, week 0–36(n=87)* Required† (n=9) Not Randomized‡ (n=6) week 10–36(n=34) week 10–36(n=37) ABR, median Prestudy 5 12 5.5 3 2 Study 2.82 8.7 0.75 1.48 2.88 P value 0.0015 0.2445 0.0766 0.0039 0.4981 AJBR, median Prestudy 2 9 3.5 2 2 Study 1.46 7.24 0 1.40 1.39 P value 0.0045 0.3484 0.0673 0.0131 0.4111 P values (paired Student’s t test) are nominal, as no multiplicity control was applied. *n=86 for AJBR. †Patients with ≥2 breakthrough bleeds in weeks 0–10. ‡Patients with ≤1 bleeds in weeks 0–10 who were not randomized (randomized arms were filled). Conclusions: BAY 94-9027 prophylaxis resulted in lower ABRs and AJBRs during the 36-week study period compared with prestudy values in patients previously treated with prophylaxis. Subgroup analyses based on prophylactic dosing regimens (including dosing intervals of up to every 7 days) showed that patients who were randomized based on bleeding phenotype during the 10-week run-in period achieved bleeding control that was better than or comparable to their prestudy levels, highlighting the value of individualized phenotype-based dosing with BAY 94-9027. In addition, prophylaxis with BAY 94-9027 resulted in reduced joint, spontaneous, and trauma bleeds compared with on-demand treatment. Disclosures Boggio: Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, and Pfizer: Consultancy. Hong:Bayer HealthCare: Employment. Wang:Bayer HealthCare Pharmaceuticals: Employment. Michaels:Bayer HealthCare Pharmaceuticals: Employment.

Pharmacokinetics of BAX 826, a Polysialylated Full-Length rFVIII, in Hemophilia a Mice, Rats, and Cynomolgus Monkeys

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1073-1073 ◽  
Author(s):  
Alexandra Schiviz ◽  
Gerald Hoebarth ◽  
Martin Wolfsegger ◽  
Paolo Rossato ◽  
Alfred Weber ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Geometric Mean ◽  
Pharmacokinetic Profile ◽  
Activity Level ◽  
Full Length ◽  
Pharmacokinetic Parameters ◽  
Sprague Dawley ◽  
Target Dose ◽  
Cynomolgus Monkeys ◽  
Fviii Activity

Abstract Factor VIII (FVIII) is a critical component of the intrinsic coagulation pathway. Plasma-derived or recombinant (r) FVIII concentrates are used in patients with hemophilia A to provide a FVIII level sufficient to treat and prevent bleeding episodes. Prophylactic FVIII levels can only be maintained by administering several infusions per week. Extended FVIII circulation times would reduce the frequency of infusions, increase patient compliance, reduce the number of bleeds, and offer the possibility to achieve higher trough levels of FVIII. Prolonged circulation can be achieved by modifying the FVIII molecule with hydrophilic polymers, for example with polysialic acid (PSA). BAX 826, Baxalta's polysialylated FVIII is based on ADVATE, a full length recombinant FVIII molecule with an established extensive safety and efficacy profile. The aim of the presented studies was to assess the pharmacokinetic profile of BAX 826 in hemophilia A mice, wild-type rats, and cynomolgus monkeys. Unmodified rFVIII (ADVATE) was used as the reference compound. Test and reference compounds were administered at the same dose. Hemophilia A mice and Sprague Dawley rats were intravenously injected with BAX 826 at a target dose of 200 IU/kg rFVIII, and blood was sampled pre-dose and 5 min to 48 h after administration. Cynomolgus monkeys received a target dose of 350 IU/kg rFVIII and blood sampled 5 min to 120 h after administration. Citrated plasma was prepared and analyzed for FVIII activity (chromogenic), FVIII antigen (ELISA), and PSA-rFVIII concentration. The primary endpoint was area under the curve from administration time to the last quantifiable time point (AUC0-tlast). Mean residence time (MRT) and systemic clearance (CLs) were also assessed. Unless stated otherwise, results for FVIII activity (mice, monkeys) and FVIII antigen (rats) are presented. In mice, the AUC0-tlast for BAX 826 was 20.6 h*IU/mL, which was 2.4 times larger than for ADVATE (8.71 h*IU/mL); MRT was 10.6 h for BAX 826 and 5.8 h for ADVATE. Clearance was lower for BAX 826 (9.4 vs. 22.3 mL/h/kg). In rats, the AUC0-tlast for BAX 826 was 18.0 h*IU/mL, which was 1.8 times larger than for ADVATE (9.9 h*IU/mL). MRT was 12.5 h for BAX 826 and 4.0 h for ADVATE, and CLs was 5.3 and 28.1 mL/h/kg. In monkeys, the geometric mean of AUC0-tlast was 189.0 h*IU/mL for BAX 826 and 39.6 h*IU/mL for ADVATE. MRT was 23.4 and 10.1 h, and CLs was 2.25 and 6.72 mL/h/kg for BAX 826 and ADVATE, respectively. In monkeys, a baseline FVIII activity level was detected and adequately taken into account in calculating pharmacokinetic parameters. Nevertheless, to better follow the pharmacokinetic profile of BAX 826, the polysialylated rFVIII concentration was also assessed using a PSA specific assay. PSA-FVIII was measured in all animals after administration of BAX 826. In summary, pharmacokinetics studies in three animal species provided evidence that modification of ADVATE with PSA increases circulation time and exposure compared with the unmodified protein. Disclosures Schiviz: Baxalta Innovations GmbH: Employment. Hoebarth:Baxalta Innovations GmbH: Employment. Wolfsegger:Baxalta Innovations GmbH: Employment. Rossato:Baxalta Innovations GmbH: Employment. Weber:Baxalta Innovations GmbH: Employment. Gritsch:Baxalta Innovations GmbH: Employment. Rottensteiner:Baxalta Innovations GmbH: Employment. Turecek:Baxalta Innovations GmbH: Employment. Scheiflinger:Baxalta Innovations GmbH: Employment. Hoellriegl:Baxalta Innovations GmbH: Employment. Putz:Baxalta Innovations GmbH: Employment.

scholarly journals Pharmacokinetics of Darunavir at 900 Milligrams and Ritonavir at 100 Milligrams Once Daily when Coadministered with Efavirenz at 600 Milligrams Once Daily in Healthy Volunteers

2010 ◽  
Vol 54 (7) ◽  
pp. 2775-2780 ◽  
Author(s):  
Gaik H. Soon ◽  
Ping Shen ◽  
Eu-Leong Yong ◽  
Paul Pham ◽  
Charles Flexner ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Half Life ◽  
Geometric Mean ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type ◽  
Time Curve ◽  
Once Daily ◽  
Drug Concentrations ◽  
Trough Concentrations

ABSTRACT Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC50) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC0-24) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC0-24 (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC0-24 when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC50 for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

scholarly journals Pharmacokinetics of Solithromycin (CEM-101) after Single or Multiple Oral Doses and Effects of Food on Single-Dose Bioavailability in Healthy Adult Subjects

2011 ◽  
Vol 55 (5) ◽  
pp. 1997-2003 ◽  
Author(s):  
J. Gordon Still ◽  
Jennifer Schranz ◽  
Thorsten P. Degenhardt ◽  
Drusilla Scott ◽  
Prabhavathi Fernandes ◽  
...  
Keyword(s):  
Phase 1 ◽  
Pharmacokinetic Profile ◽  
Time Curve ◽  
Time To Peak ◽  
Dose Study ◽  
Human Pharmacokinetic ◽  
The Mean ◽  
Double Blinded ◽  
Oral Doses

ABSTRACTThe pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 μg/ml to 19.647 μg/ml, and the area under the concentration-versus-time curve from time zero to timet(AUC0–t) ranged from 0.0402 μg · h/ml to 28.599 μg · h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 μg/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUCτ) ranged from 2.310 to 18.41 μg · h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. MedianTmaxvalues remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with itsin vitropotency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin.

scholarly journals 631. Preliminary safety and pharmacokinetic profile of VIR-2482: a monoclonal antibody for the prevention of influenza A illness

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S376-S376
Author(s):  
Jennifer Sager ◽  
David K Hong ◽  
Aurelio Bonavia ◽  
Lynn Connolly ◽  
Deborah Cebrik ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Single Dose ◽  
Half Life ◽  
Influenza A ◽  
Phase 1 ◽  
Safety Data ◽  
Phase 2 ◽  
Independent Contractor ◽  
Post Dose ◽  
Phase 2 Study

Abstract Background VIR-2482 is a fully human immunoglobulin G1(IgG) monoclonal antibody (mAb) directed against a highly-conserved epitope in the influenza A hemagglutinin stem region and is in clinical development for the prevention of influenza A illness. The Fc region of VIR-2482 has been modified to provide an extended half-life. Methods This is a randomized, placebo-controlled, Phase 1/2 study of VIR-2482 administered intramuscularly (IM) to healthy adult volunteers aged 18-64 years old who have not received a current influenza vaccine. The Phase 1 portion of the study will evaluate the safety, tolerability, pharmacokinetic (PK), and immunogenicity profile of VIR-2482 following single (Part A) or multiple doses (Part B). The Phase 2 study will evaluate the efficacy of VIR-2482 in the prevention of influenza A illness as well as safety, tolerability, and PK. Part A is ongoing and consists of four single dose cohorts (N=25/cohort) randomized (4:1) to a single dose of VIR-2482 or placebo at 60, 300, 1200, or 1800 mg. Safety, tolerability, PK and immunogenicity will be evaluated for at least 52 weeks post-dose. Results In Part A, all 100 subjects received a single dose of VIR-2482 (N=80) or placebo (N=20). Preliminary blinded safety data for all cohorts and PK data for the 300 and 1200 mg cohorts are reported here. Dosing was well tolerated; 6% (6/100) of subjects experienced mild injection site reactions, which generally resolved within 48 hrs. Through 12 weeks post-dosing, the majority (124/126; 98.4%) of adverse events (AEs) were mild to moderate in nature, no serious AEs were reported, and no subjects discontinued due to an AE. Based on available data, exposure (Cmax and AUC) between 300 and 1200 mg of VIR-2482 increased in a dose proportional manner. The PK profile of VIR-2482 is consistent with a half-life extended IgG. Conclusion Based on available data, VIR-2482 has been well tolerated following single IM doses of up to 1800 mg in healthy subjects. The preliminary PK profile of VIR-2482 enables once per season dosing. Overall, these data support initiation of a Phase 2 study to evaluate efficacy of VIR-2482 for the prevention of influenza A illness. Disclosures Jennifer Sager, PharmD, Vir Biotechnology (Employee) David K. Hong, MD, Vir Biotechnology (Employee) Aurelio Bonavia, PhD, Vir Biotechnology (Employee) Lynn Connolly, MD, PhD, Vir Biotechnology (Employee) Deborah Cebrik, PhD, Vir Biotechnology (Independent Contractor) Marie Christine Fanget, MS, Vir Biotechnology (Employee) Erik Mogalian, PharmD, PhD, Vir Biotechnology (Employee)

scholarly journals Population Pharmacokinetic Modeling and Simulation of Recombinant Single-Chain Factor VIII (r VIII-SingleChain) in Patients with Hemophilia a

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2814-2814
Author(s):  
Ying Zhang ◽  
Tharin Limsakun ◽  
Debra M. Bensen-Kennedy ◽  
Alex Veldman ◽  
Zhenling Yao
Keyword(s):  
Body Weight ◽  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Fviii Activity ◽  
Dosing Regimens ◽  
Trough Levels ◽  
Plasma Activity

Abstract Introduction: Hemophilia A is a rare but serious X-linked recessive bleeding disorder that affects males and is characterized by a deficiency in the plasma protein known as coagulation Factor VIII. rVIII-SingleChain is a proprietary, lyophilized formulation of clotting factor VIII (FVIII) produced by recombinant technology. As part of the clinical development of rVIII-SingleChain, a population pharmacokinetic (PK) analysis was undertaken, utilizing data from Study CSL627_1001 in subjects with hemophilia A, with the objectives of (a) characterizing the PK of rVIII-SingleChain at a population level, (b) assessing the ability of various patient characteristics (e.g., von Willebrand factor, VWF) to describe variability in the PK parameters, and (c) enable population-based simulations of rVIII-SingleChain dosing regimens that may provide improved prophylaxis coverage compared with octocog alfa (Advate®). Methods: Twenty-seven male subjects (aged 19-60 years) enrolled in Study CSL627_1001 (Part 1) received a single 50 IU/kg IV infusion of Advate®, followed by a single 50 IU/kg IV infusion of rVIII-SingleChain, with a minimum 4-day washout period. Plasma PK samples (for the determination of FVIII activity) were collected over 72 hours for both Advate® and rVIII-SingleChain (at pre-specified time points) and were measured by a validated chromogenic assay. Population PK models were developed separately for rVIII-SingleChain and Advate®, using the NONMEM 7 with FOCEI method. Various covariates, including VWF, body weight, and effect of age on clearance (CL) and volume of distribution were tested. Bootstrap and visual predictive check (VPC) were used for model evaluation. Simulations of different dosing regimens were performed to evaluate the FVIII activity plasma exposure profiles that may provide improved prophylaxis coverage. Results: A two-compartmental model with first-order elimination was developed to describe FVIII plasma activity data for both rVIII-SingleChain and Advate®. VWF was found to be a significant covariate influence on FVIII plasma activity CL, whilst body weight influenced both CL and volume of distribution in the central compartment. Population parameter estimates indicated a lower CL (2.02 vs 2.49 dL/h) and longer half-life (13.1 vs 9.3 h) for rVIII-SingleChain compared with Advate®. The results of bootstrap and VPC implied that the model was stable, and the parameters were estimated with good precision. PK simulations indicated that rVIII-SingleChain, at the same doses and frequencies, resulted in higher FVIII plasma activities throughout the dosing period, as reflected in higher area-under-the-curve (AUC). The dosing regimens for the simulations were designed based on the dosing recommendations of the Advate® label and rVIII-SingleChain phase III study. The results showed that rVIII-SingleChain provided a higher percentage of subjects with trough levels of at least 1% FVIII plasma activity, compared with Advate® at the same dosing regimen. Every 3 days dosing at 40-50 IU/kg rVIII-SingleChain was predicted to achieve similar prophylaxis protection compared with Advate® every 2 days (i.e., about 90% of subjects with trough levels of at least 1% FVIII plasma activity). In addition, 73-90% of subjects were predicted to achieve trough levels of at least 1% FVIII plasma activity with twice weekly dosing (4- and 3-day schedule) at 50 IU/kg rVIII-SingleChain, compared with 65-80% of subjects dosed with Advate® using the same regimen. Conclusion: The population model shows that rVIII-SingleChain has a longer half-life, lower CL and higher AUC compared with Advate®. Simulations demonstrated that rVIII-SingleChain resulted in higher trough concentrations when compared with Advate®, indicating the possibility of greater prophylaxis coverage. Disclosures Zhang: CSL Behring: Employment. Limsakun:CSL Behring: Employment. Bensen-Kennedy:CSL Behring: Employment. Veldman:CSL Behring GmbH: Employment. Yao:CSL Behring: Employment.

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