Pharmacokinetics of Intravenous Infusion of Glu-Plasminogen Concentrate in Patients with Hypoplasminogenemia

Abstract Background: Hypoplasminogenemia is a rare multisystem disease associated with fibrous deposition on mucous membranes throughout the body, primarily affecting the eyes, ears, sinuses, tracheobronchial tree, genitourinary tract, and gingiva. The best defined clinical manifestation of hypoplasminogenemia is ligneous conjunctivitis, which is characterized by thick, woody (ligneous) growths on the conjunctiva of the eye. Several genetic defects leading to plasminogen deficiency have been identified. Replacement therapy with exogenous plasminogen can achieve resolution of the lesions, but no approved replacement product is available. ProMetic BioTherapeutics, Inc. (ProMetic) is developing a lyophilized human Glu-plasminogen for systemic treatment of hypoplasminogenemia. No pharmacokinetic (PK) data for Glu-plasminogen in plasminogen-deficient patients are available in the literature. However, PK parameters may vary among patients, depending on mutation type or presence of active lesions. The current Phase I dose escalation study is being conducted to provide data on the pharmacokinetic profile and safety of this plasminogen product in patients with hypoplasminogenemia. Methods: Patients with hypoplasminogenemia (plasminogen activity level ≤40% of normal values) received a single IV infusion of 2 mg/kg of plasminogen as the first dosing cohort of a clinical study titled "A Phase 1, Dose Escalation, and Pharmacokinetic Study of ProMetic Plasminogen Administered as Intravenous Infusion in Adults and Children with Hypoplasminogenemia." The initial dose was chosen based on data generated in the GLP toxicology studies performed with the molecule. The product was supplied in 50 mL vials at a concentration of 6.3 mg/mL, which was reconstituted in 12.5 mL of sterile water for injection. The final concentration of reconstituted plasminogen was 5 mg/mL. Blood samples for PK analysis were taken 30 min prior to dosing, and then at 15 minutes, 1, 6, 24, 48, 72, 96, 120, 168, and 216 hours after infusion. This data is part of a planned analysis after completion of cohort 1 including 5 individuals. Results: Five patients (1 male, 4 females), median age 24 (range 14-38) years received a mean (±SD) volume of 26.6 ± 5.2 ml of plasminogen solution, infused over 10 minutes. Plasminogen activity levels increased from a mean of 34.6 ± 3% to 70.4 ± 7.7% at 15 minutes and slowly decreased to a mean of 45 ± 5.9% at 48 hours (reference range, 70-130%). Plasminogen activity levels for individual patients are shown in Figure 1 below. PK parameters for plasminogen activity through 48 h are shown in Table 1 below. No adverse events considered possibly related to the product were reported following intravenous administration of 2 mg/kg plasminogen. At day 30 no patient exhibited antibodies to plasminogen. Conclusions: ProMetic's lyophilized Glu-plasminogen administered at 2 mg/kg can be given safely to patients with plasminogen deficiency. PK parameters after infusion of 2 mg/kg of plasminogen support moving forward with the next dosing cohort in the clinical trial (6 mg/kg). These data represent the first PK profiles for Glu-plasminogen in plasminogen-deficient patients. The half-life was 27.2 hours, compared with the half-life of 3-4 hours previously reported for Lys-plasminogen in plasminogen-deficient patients. Table 1. PK parameters for plasminogen activity after infusion of 2 mg/kg plasminogen solution in 5 patients with hypoplasminogenemia Geometric mean (95% CI) Half-life (h) 27.2 (16.2-45.7) Cmax (%) 35 (27-46) AUClast (h*%) 935 (683-1280) AUCINF (h*%) 1359 (797-2317) Vz (µg/%/kg)a 57.7 (47.7-69.8) Cl (µg/(h*%)/kg)a 1.47 (0.86-2.51) MRTlast (h) 17.5 (15.0-20.5) MRTINF (h) 38.1 (22.0-65.9) HL, half-life; AUClast, area under the curve up to last measurable concentration; AUCINF, AUC extrapolated to infinity; Vz, volume of distribution; Cl, clearance; MRTlast, mean residence time to the last sampling time; MRTINF, MRT extrapolated to infinity. aPK analysis was performed with plasminogen activity in %; therefore, units cannot be reduced. Figure 1. Plasminogen activity after infusion of 2 mg/kg plasminogen solution in 5 patients with hypoplasminogenemia Figure 1. Plasminogen activity after infusion of 2 mg/kg plasminogen solution in 5 patients with hypoplasminogenemia Disclosures Hardesty: Biogen: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Prometic Biotherapeutics: Research Funding. Plum:ProMetic Biotherapeutics: Employment. Thibaudeau:ProMetic BioTherapeutics: Employment. Lee:ProMetic: Consultancy. Shapiro:ProMetic Life Science, Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octopharma, OPKO, PTC Therapeutics, Selexys: Research Funding; Baxalta, Novo Nordisk, Biogen: Membership on an entity's Board of Directors or advisory committees; Baxalta, Novo Nordisk, Biogen: Consultancy; Biogen: Speakers Bureau.

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

Blood ◽

10.1182/blood-2019-122211 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 625-625 ◽

Cited By ~ 2

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.

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Ordering Patterns of Thrombophilia Testing and Its Appropriateness

Blood ◽

10.1182/blood-2021-151923 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1890-1890

Author(s):

Lydia Chow ◽

Sarah Garvey ◽

Thomas Ma ◽

Jay Hudgins ◽

Caroline I. Piatek

Keyword(s):

Arterial Thrombosis ◽

Research Funding ◽

Protein C ◽

Pregnancy Loss ◽

Activity Level ◽

Factor V ◽

Activity Levels ◽

Test Selection ◽

Apc Resistance ◽

Thrombophilia Testing

Abstract Background Despite society recommendations to limit thrombophilia testing, this testing is often sent inappropriately. The results of thrombophilia testing frequently do not affect management. Additionally, interpretation of thrombophilia testing is confounded by acute thrombosis, anticoagulation (AC) therapy, and other medical comorbidities. Incorrect test selection is also a source of unnecessary testing [i.e. Factor V (FV) activity level instead of Factor V Leiden (FVL)]. The aim of our study was to assess ordering patterns for thrombophilia testing by qualifying the number of tests, identifying the requesting services, and assessing the appropriateness of testing. Methods This was a retrospective study of thrombophilia testing performed at LAC+USC Medical Center, Los Angeles, CA from January 1, 2019 to December 31, 2019. A laboratory query of thrombophilia testing was performed to identify eligible adult patients who received thrombophilia testing without a prior confirmed thrombophilia. Thrombophilia testing included: FVL and prothrombin 20210 gene mutations; activated protein C (APC) resistance; antithrombin, or protein C or S activity levels; and antiphospholipid syndrome (APS) evaluation with lupus anticoagulant, cardiolipin (CL) immunoglobulins IgM/G, and beta-2 glycoprotein (b2gp) IgM/IgG; and JAK2 V617F mutation. Homocysteine (HC) levels and methylenetetrahydrofolate reductase (MTHFR) gene mutation testing were considered to have limited clinical utility. FV activity and phosphatidylserine IgM/IgG were considered incorrect tests. The electronic medical record was reviewed for clinical history, indication for testing, requesting service, and appropriateness. The criteria for defining appropriateness were determined based on major society guidelines and literature review. The main criteria are summarized here. Testing was considered inappropriate for a provoked venous thromboembolism (VTE) or stroke/transient ischemic attack (TIA). For unprovoked VTE, testing was considered inappropriate for patients > 45 yo except for APS testing. For non-stroke arterial thrombosis, recurrent pregnancy loss or stillbirth, and diagnostic evaluation of suspected lupus, APS testing only was considered appropriate. Results 450 patients underwent thrombophilia testing with a mean age of 42 (range: 18-90); 76% were female and 81% were Hispanic. A total of 1698 thrombophilia tests were sent by 27 services. Testing was done in the following settings: inpatient (40%), outpatient (59%), and emergency department (1%). The mean tests per patient were 3.7 (range: 1-12). The most common requesting services were rheumatology (24%), obstetrics-gynecology (19%), and internal medicine/medicine-pediatrics (14%). Hematology requested 10% of tests. Common indications for testing were VTE (21%), rheumatology-related (25%), pregnancy-related (13%), ischemic stroke/TIA (9%), ocular-related (7%), non-stroke arterial thrombosis (3%), and dermatology-related (4%) (Table 1). 5% (84 tests) were sent for the evaluation of other non-thrombotic conditions. 8% (132 tests) were sent for > 1 indication, such as concurrent arterial and venous events. 840 tests (49%) were deemed inappropriate. Common reasons for inappropriate testing included provoked VTE events, stroke/TIA, APS testing after first pregnancy loss, current AC, and duplicate testing (Table 2). APS testing issues included testing for LAC while on AC, incomplete testing (both CL and b2GP not sent), incorrect tests (phosphatidylserine IgM/IgG), and repeat testing < 12 weeks from prior. Incorrect/redundant testing for FVL included: FV activity levels (36 total tests; 9 ordered in additional to FVL and 27 ordered instead of FVL) and APC resistance ordered simultaneously with FVL in 7 patients. Of note, 92 tests were sent for evaluation of non-thrombotic conditions. Conclusions Thrombophilia testing is often done inappropriately. Correct test selection is also a relatively common issue, particularly with APS and FVL testing. Given the large number of services ordering thrombophilia testing at our training hospital and this testing being sent for a variety of reasons, it is unlikely that physician education alone will lead to a substantial or sustained decrease in the number of inappropriate tests. Rather, it may be necessary to restrict at least some thrombophilia testing to certain services. Figure 1 Figure 1. Disclosures Piatek: Rigel: Consultancy, Research Funding; Alexion: Consultancy, Research Funding; Apellis: Research Funding; Dova: Consultancy, Speakers Bureau.

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Do e-athletes move? A study on physical activity level and body composition in elite e-sports

Physical Education of Students ◽

10.15561/20755279.2020.0501 ◽

2020 ◽

Vol 24 (5) ◽

pp. 259-264

Author(s):

Akan Bayrakdar ◽

Yağmur Yıldız ◽

Işık Bayraktar

Keyword(s):

Physical Activity ◽

Body Composition ◽

South Korea ◽

Physical Activity Level ◽

Body Height ◽

The United States ◽

The Body ◽

Activity Level ◽

Activity Levels ◽

Significant Difference

Background and Study Aim. The aim of this study is to determine the effect of e-sports on physical activity level and body composition. Material and Methods. The athletes who participated in the study were 19.92± 2.21 years of age, 1.73±0.04 m body height and 78.35±6.52 kg body weight. A total of 137 athletes participated in the study, including 27 from Turkey, 47 from South Korea and 63 from the United States (USA). The data was collected by e-mail from the sports clubs. The athletes who representing their country in international competitions involved in the study. The data obtained were evaluated in the SPSS program. Results. According to the findings of the study, the body mass index (BMI) of e-sport athletes is 26.03±1.85, the number of physical activity steps is 6646±3400 and the daily e-sport hours are 9.34±1.12. The BMI was determined as USA 26.12, South Korea 26.02 and Turkey 25.84 respectively. The number of physical activity steps was identified as 5255 steps in the US, 7785 steps in South Korea and 7909 steps in Turkey. The daily e-sports hour is set at US 9.63 hours, Turkey 9.29 hours and South Korea 8.97 hours. In comparison of country-based athletes, there was a significant difference between physical activity level and daily e-sports hours at p<0.05. The value of BMI is not different. Although it is not statistically related to the physical activity level and BMI. There was no statistically significant relationship between daily e-sports hours and BMI and physical activity step counts. However, as the time of e-sports increases, BMI increases and the number of physical activity steps decreases. Conclusions. As a result it is seen in the findings of the research that athletes dealing with e-sports are included in the fat group as a body composition and their daily physical activity steps are low. In addition, according to the results of the research, e-sports are thought to have negative effects on physical health. Thanks to the physical activity programs to be applied to these athletes, it is thought that their body composition and physical activity levels can be improved.

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Cirmtuzumab (UC-961), a First-in-Class Anti-ROR1 Monoclonal Antibody: Planned Interim Analysis of Initial Phase 1 Cohorts

Blood ◽

10.1182/blood.v126.23.1736.1736 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1736-1736 ◽

Cited By ~ 2

Author(s):

Michael Y. Choi ◽

George F. Widhopf ◽

Januario Castro ◽

Hongying Li ◽

Reilly L Kidwell ◽

...

Keyword(s):

Disease Progression ◽

Dose Escalation ◽

Receptor Tyrosine Kinase ◽

Half Life ◽

Initial Phase ◽

Research Funding ◽

Post Partum ◽

Phase 1 ◽

Advisory Board ◽

Orphan Receptor

Abstract INTRODUCTION: Chronic lymphocytic leukemia (CLL) cells of nearly all patients (pts) express ROR1 (Receptor tyrosine kinase-like Orphan Receptor 1), an orphan-receptor tyrosine-kinase-like protein that is normally expressed during embryogenesis, but not by normal post-partum tissues. ROR1 is a receptor for Wnt5a, which can induce non-canonical Wnt signaling to enhance CLL-cell survival and/or proliferation. We have developed antibodies that bind to epitopes that span the extracellular portion of human ROR1, and selected one mAb that had the most potent activity in inhibiting such signaling. We fully humanized this antibody to generate UC-961 (cirmtuzumab). GLP-compliant studies demonstrated that this antibody does not cross-react with normal post-partum tissues. Preclinical pharmacology/toxicology studies in Sprague-Dawley rats showed no evidence of toxicity for cirmtuzumab at doses up to 400 mg/kg by IV administration with an apparent half-life exceeding 7 days. Studies in cynomolgus monkeys again showed no apparent toxicity with an antibody half-life of approximately 14 days. Based on these IND-enabling studies, we have initiated a first-in-human phase 1 dose escalation study to determine the safety and tolerability of cirmtuzumab in the treatment of pts with relapsed or refractory CLL. Here, we report results of planned interim safety analysis of pts in the initial phase 1 cohorts. METHODS: Key eligibility criteria included relapsed or refractory CLL and indication for therapy according to working group guidelines (iwCLL). The starting dose was 15 mcg/kg, based on preclinical modeling of 30% target saturation. Cirmtuzumab was administered every 14 days for a total of 4 doses, with intra-patient dose escalation in the absence of toxicity. Patients were enrolled in cohorts of 3 to 6 patients, with the most recently completed cohort receiving doses of 0.5 mg/kg to 1 mg/kg. Pre-planned analysis of safety and tolerability was conducted at the completion of a 56-day dose-limiting toxicity observation period. RESULTS: Between August 2014 and July 2015, 10 pts have received cirmtuzumab. The median age of the treated pts was 72 (range 58 to 81); the median number of prior therapies was 4 (ranging from 1-9). Nine pts had at least 1 high-risk prognostic factor, including leukemia-cell expression of ZAP-70 (4 pts), unmutated IGHV (5 pts), del(17p) or complex karyotype (5 pts). Cirmtuzumab was well tolerated. We have not observed ≥ grade 2 drug-related adverse events (AE) in any of the treated pts. The only grade 1 drug-related AE that occurred in more than 1 pt was anemia (3 pts), all of which resolved. One patient came off study due to continued disease progression after receiving a single dose of 15 mcg/kg; the rest of the pts received all four doses of cirmtuzumab, as per protocol. The low dose administered to patients in the first few cohorts precluded us from detecting sufficient cirmtuzumab in the plasma for pharmacokinetic studies. However, cirmtuzumab was detected in the plasma of pts in later cohorts, allowing us to estimate a half-life for cirmtuzumab of approximately 14 days. Response was assessed as per iwCLL criteria 2 months after the final dose of cirmtuzumab. 3 pts have not yet reached that time point, and 1 pt was not evaluable due to progresison and early study discontinuation. Of the 6 pts evaluable for response, 2 experienced continued disease progression and 4 met criteria for stable disease. With a median follow-up of 103 days after the completion of cirmtuzumab, 2 pts that had disease progression have required additional therapy; the other 4 have yet to require additional treatment. CONCLUSIONS: Cirmtuzumab is a first-in-class anti-ROR1 monoclonal antibody. In a phase 1 dose-escalation trial, pts with relapsed or refractory CLL have tolerated cirmtuzumab well, without any drug-related grade 2 or higher AEs. This is consistent with the preclinical profile and lack of target expression in normal tissues. The ongoing phase 1 study will evaluate the safety and tolerability of higher doses to determine the maximum tolerated dose or biologically optimal dose of cirmtuzumab. Disclosures Choi: Gilead: Consultancy, Other: Advisory Board, Speakers Bureau; AbbVie: Consultancy, Other: Advisory Board, Research Funding. Jamieson:J&J: Research Funding; GSK: Research Funding. Kipps:Gilead: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; AbbVie: Consultancy, Research Funding.

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Pharmacokinetic Characterisation Of Recombinant FXIII Across Age Groups In Patients With FXIII Subunit A Congenital Deficiency

Blood ◽

10.1182/blood.v122.21.3613.3613 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3613-3613

Author(s):

Brigitte Brand-Staufer ◽

Manuel Carção ◽

Bryce A. Kerlin ◽

Diane Nugent ◽

Andrew Will ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Geometric Mean ◽

Age Groups ◽

Activity Levels ◽

Phase 3 ◽

Advisory Committees ◽

Post Dose ◽

Congenital Deficiency ◽

Fxiii Activity

Abstract Introduction Three trials, F13CD-1725, F13CD-3760 and F13CD-3720 have investigated the pharmacokinetics (PK) of recombinant FXIII (rFXIII), given at a dose of 35 IU/kg once monthly, in a total of 54 patients with FXIII congenital deficiency (Inbal A et al Blood 2012;119(22):5111-5117; Williams M et al Haemophilia 2013;DOI:10.1111/hae.12224; Kerlin B et al JTH 2013;11(Suppl 2):235-236). The aim of the current analysis was to assess and compare the PK characteristics of rFXIII among trials and 3 different age groups of patients (1-<6, 6-17 and ≥18 years). Methods All patients were dosed with rFXIII 35 IU/kg every 4th week. Blood samples for PK assessments were collected regularly throughout the dosing interval (28 to 30-day period) in the 3 trials: in the pivotal phase 3 trial, F13CD-1725, at 1 hour, 14 and 28 days post-dose; in the paediatric F13CD-3760 trial at 0.5 and 24 hours and 7, 14, 21 and 30 days post-dose; and in the F13CD-3720 phase 3 extension trial at 1 and 2 hours and 3, 7, 14, 21 and 28 days post-dose. Prior to the PK assessment, all but 2 patients had received treatment with repeated doses of either plasma derived FXIII products or rFXIII, thus all PK measurements were performed at steady-state. The Berichrom® FXIII activity assay was used for measurement of FXIII activity. PK parameters were calculated using non-compartmental statistical methods, without baseline adjustment. The results include data from a total of 54 patients, aged 1 to 60 years; 41 in the F13CD-1725 trial, 23 in the F13CD-3720 trial (including 16 patients who also participated in F13CD-1725), and 6 in the F13CD-3760 trial. Results The non-compartmental PK parameters (Cmax, Ctrough, AUC0-28/30d, t1/2) were similar across the 3 age groups (Table 1). Post-hoc, pairwise t-tests across the age groups of log-transformed data did not demonstrate any statistically significant differences, when adjusting p-values for multiple testing. Additionally, separate ANOVA analyses of each of the parameters, showed no significant differences across the groups. The geometric mean half-life ranged from 11.6 to 15.0 days (Figure 1), and the trough FXIII activity levels ranged from 0.15 to 0.21 IU/mL (Figure 2). The geometric mean recoveries were also in the same range; 0.015 (F13CD-1725), 0.013 (F13CD-3760) and 0.020 (F13CD-3720) (IU/mL)/(IU/kg). Furthermore, it could be demonstrated that the mean PK profiles were similar for the 3 trials, and that Cmax and Ctrough values, as well as FXIII exposures (AUC), were constant over time, based on results from patients participating in both the F13CD-1725 and the F13CD-3720 trial. Conclusion The PK profile of rFXIII, after dosing with 35 IU/kg of rFXIII, was independent of age and comparable between trials. It was further demonstrated that FXIII trough activity levels were constant over time, when comparing the individual levels of FXIII activity in patients participating in both the F13CD-1725 and the F13CD-3720 trials. Despite rather large individual variation (CV of up to 38%) in the maximal FXIII activity levels, all individual mean trough activity levels were above 0.1 IU/mL during the entire duration of the trials. The results support that monthly dosing with 35 IU/kg of rFXIII to patients with FXIII subunit A deficiency, regardless of age, is adequate for prophylaxis. Nevertheless individual PK measurements to determine optimal dose and dosing frequency should be considered due to patient variation. Disclosures: Brand-Staufer: Bayer HealthCare: Travel support, Travel support Other; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel support Other; Bayer: DMC Chair for a Bayer study Other. Carção:Octapharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, Travel Support. Other; CSL Behring: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Travel Support., Travel Support. Other; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Scientific Advisory Board. Travel Support., Speakers Bureau, Travel Support. Other; Novo Nordisk: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Support., Travel Support. Other; Biogen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel Support., Travel Support. Other; Bayer : Honoraria, Research Funding, Travel Support. , Travel Support. Other; Baxter: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Support. Other. Kerlin:Bayer HealthCare: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Research Funding. Nugent:Novo Nordisk: Honoraria; CSL Behring: Honoraria; Bayer: Honoraria. Will:Novo Nordisk: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Williams:Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Travel support., Travel support. Other; Bayer: Travel support, Travel support Other; Baxter: Membership on an entity’s Board of Directors or advisory committees, Travel support. Other. Rosholm:Novo Nordisk: Employment. Sandberg Lundblad:Novo Nordisk: Employment.

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A different point of view: the evaluation of motor imagery perspectives in patients with sensorimotor impairments in a longitudinal study

BMC Neurology ◽

10.1186/s12883-021-02266-w ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Szabina Gäumann ◽

Rahel Sarah Gerber ◽

Zorica Suica ◽

Jasmin Wandel ◽

Corina Schuster-Amft

Keyword(s):

Longitudinal Study ◽

Motor Imagery ◽

Point Of View ◽

The Body ◽

Activity Level ◽

Patient Specific ◽

Activity Levels ◽

Explanatory Variables ◽

Training Interventions ◽

Movement Type

Abstract Background Motor imagery (MI) has been successfully applied in neurological rehabilitation. Little is known about the spontaneous selection of the MI perspectives in patients with sensorimotor impairments. What perspective is selected: internal (first-person view), or external (third-person view)? The aim was to evaluate the MI perspective preference in patients with sensorimotor impairments. Methods In a longitudinal study including four measurement sessions, 55 patients (25 stroke, 25 multiple sclerosis, 5 Parkinson’s disease; 25 females; mean age 58 ± 14 years) were included. MI ability and perspective preference in both visual and kinaesthetic imagery modalities were assessed using the Kinaesthetic and Visual Imagery Questionnaire-20 (KVIQ-20), the body rotation task (BRT), and mental chronometry (MC). Additionally, patients’ activity level was assessed. Descriptive analyses were performed regarding different age- (< 45, 45–64, > 64), activity levels (inactive, partially active, active), and KVIQ-20 movement classifications (axial, proximal, distal, upper and lower limb). A mixed-effects model was used to investiage the relationship between the primary outcome (MI perspective: internal, external) with the explanatory variables age, MI modality (visual, kinaesthetic), movement type (axial, proximal, distal), activity levels and the different assessments (KVIQ-20, BRT, MC). Results Imagery modality was not a significant predictor of perspective preference. Over the four measurement sessions, patients tended to become more consistent in their perspective selection, however, time point was not a significant predictor. Movement type was a significant predictor: imagination of distal vs. axial and proximal vs. axial movements were both associated with preference for external perspective. Patients with increased physical activity level tend to use internal imagery, however, this effect was borderline not statistically significant. Age was neither a significant precictor. Regarding the MI assessments, the KVIQ- 20 score was a significant predictor. The patients with higher test scores tend to use the external perspective. Conclusion It is recommended to evaluate the spontaneous MI perspective selection to design patient-specific MI training interventions. Distal movements (foot, finger) may be an indicator when evaluating the consistency of the MI perspective in patients with sensorimotor impairments.

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Effect of Seat Backrest Inclination on the Muscular Pattern and Biomechanical Parameters of the Sit-to-Stand

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.678302 ◽

2021 ◽

Vol 15 ◽

Author(s):

Nadège Tebbache ◽

Alain Hamaoui

Keyword(s):

Kinematic Chain ◽

The Body ◽

Activity Level ◽

Lower Limbs ◽

Upper Body ◽

Whole Body ◽

Activity Levels ◽

Phase Duration ◽

Sit To Stand ◽

Biomechanical Parameters

Objectives: The sit-to-stand (STS) transfer mobilizes an extended part of the kinematic chain throughout a postural phase characterized by a flexion of the trunk and a focal phase consisting of a whole-body extension. The aim of this study was to analyze the variations of the global muscular pattern and the biomechanical parameters in both phases, in relation with seat backrest inclination.Methods: Fifteen participants were asked to stand up from a seat with 5 backrest inclination settings and at 2 execution speeds. The ground reaction forces and the activity levels of fifteen muscles of the trunk and lower limbs were investigated.Results: Backrest-induced modifications were mainly observed in the postural phase: inclining the backrest backward increased the phase duration and the activity level of the sternocleidomastoideus and the rectus abdominis, while it reduced the activity of the tibialis anterior. It also allowed for an increased maximal anteroposterior velocity of the body center of mass. Higher execution speed led to increased and earlier muscular activities of many trunk and lower limbs muscles, predominantly in the postural phase.Discussion: Taken together, these results suggest that a greater backrest inclination increases the demand in the postural phase due to the increase of the upper body gravity torque about the ischial tuberosities, and requires an adaptation of muscular activity levels and timing, but with the same overall pattern. The kinetic energy gained during the longer excursion of the trunk may also require less activation of the lower limbs muscles involved in the generation of propulsive forces of the body.

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Preliminary Safety, Pharmacokinetics (PK) and Pharmacodynamic (PD) Analysis of the Polo-like Kinase-1 (PLK1) Inhibitor PCM-075, in Combination with Low-Dose Cytarabine (LDAC) or Decitabine (D) in Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood-2018-99-112590 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4043-4043

Author(s):

Amer M. Zeidan ◽

Gary J. Schiller ◽

Alexander I Spira ◽

Prapti A. Patel ◽

Michaela L. Tsai ◽

...

Keyword(s):

Gene Expression ◽

Adverse Events ◽

Expression Analysis ◽

Dose Escalation ◽

Half Life ◽

Research Funding ◽

Gene Expression Analysis ◽

Phase 1 ◽

Response To Treatment ◽

Blast Cells

Abstract Background: Polo-like Kinase 1 (PLK1), a serine/threonine kinase, is a master regulator of cell-cycle progression and overexpressed in numerous cancer types including AML. In a randomized phase 2 study, a pan-PLK inhibitor, volasertib, administered IV to patients (pts) with newly diagnosed AML in combination with LDAC showed a statistically significant survival advantage compared to LDAC alone, however a subsequent phase 3 study did not reach significance. Unfavorable features of volasertib may have contributed to this outcome: a long half-life (~5 days), lack of specificity and the safety of the dosing regimen. PCM-075 is a third generation, orally active and highly selective PLK1 inhibitor with a ~24-hour half-life that demonstrates activity in preclinical AML models both as a single agent and in combination with LDAC. It is also safe and well tolerated as shown by a phase 1 trial in pts with solid tumors (Weiss et al 2018 Invest New Drugs 36:85-95). PCM-075 is currently being evaluated in a phase 1b dose-escalation trial (NCT03303339) for R/R AML in combination with either LDAC or D. The primary objective is to assess safety, PK, and the maximum tolerated dose of these drugs in combination. In addition, potential PD biomarkers for response are being explored. Methods: Pts are treated with PCM-075 for 5 days in combination with either LDAC (20 mg/m2 SC qd x 10d) or D (20 mg/m2 IV qd x 5d) over a flexible 21 to 28-day cycle. Each arm follows a standard dose escalation design with 50% increments in successive cohorts of 3 pts. Dose limiting toxicity (DLT) is evaluated during the 1st cycle. Blood samples and bone marrow (BM) biopsies are obtained within each treatment cycle for PK profiles, PD and genomic biomarker analyses. Immuno- and genomic profiles are characterized in blood and BM blast cells. Assessment of PLK1 inhibition is determined by changes in phosphorylation status of pTCTP, a PLK1 substrate. Genomic analysis (detection of fusions and mutations) and gene expression analysis (RNA-seq) are being used to identify genetic subtypes and gene expression signatures that may be associated with response to treatment. Results: As of July 20, 2018, 12 pts (9M, 3F), ages 33-88 (median 66 years) were enrolled in this trial. At the starting dose of 12mg/m2 of PCM-075, 3 pts received LDAC and 4 D. The second cohort (18mg/m2) enrolled 5 pts; 3 received LDAC and 2 received D. The median duration of treatment for all pts was 1 cycle (range 1-4 cycles); 5 pts are still ongoing. Adverse events (AEs) were evaluated for 9 pts based on available data. Events observed in more than one pt included fatigue (4), constipation (2) and nausea (2), and all were grade ≤2. Hyponatremia was reported in 2 patients, grades 1 and 3, respectively. All non-hematologic AEs were reversible and considered treatment-unrelated except for a grade 1 fatigue (1 pt) and grade 1 nausea (1 pt). Serious adverse events were reported for 5 pts as 17 separate events but none were considered treatment-related. The most frequent SAE was febrile neutropenia (3 pts). No treatment-related deaths or DLTs occurred and escalation of dosing is ongoing. PK profiles of PCM-075 in LDAC and D pts were similar to profiles obtained from pts treated with PCM-075 alone in the previous phase 1 trial, suggesting no drug interaction between PCM-075 with LDAC or D. To date, PD markers were evaluated in 8 pts. Three pts showed a significant decrease in PLK1 activity via assessment of pTCTP status 3h after treatment that was sustained after 4 daily doses of PCM-075. In these 3 pts, percent circulating blasts were reduced from 33% to 7%, 92% to 24%, and 61% to 4%. BM blasts in these pts were reduced from 75% to 60% (cycle 2), 96% to 40% (cycle 2), and 30% to 15% (cycle 1), respectively. Conversely, in pts who did not show decreases greater than 10% in either circulating or BM blasts, PLK1 inhibition was not observed, suggesting a potential correlation between PLK1 inhibition and reduction of blast cells. Conclusions: The combination of PCM-075 with either LDAC or D demonstrated safety and tolerability in the first two dose cohorts of patients with R/R AML, and further dose escalation is ongoing. Evidence of PLK1 inhibition has been observed and this appears to be correlated with systemic blast reduction. Additional clinical activity, genomic and gene expression analysis of other biomarkers associated with PLK1 inhibition and response to treatment will be provided from expanded and escalated dosing cohorts. Disclosures Zeidan: Abbvie: Consultancy; Novartis: Consultancy; Ariad: Consultancy, Speakers Bureau; Agios: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Incyte: Employment; Pfizer: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Spira:BMS: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; ADC Therapeutics: Research Funding; Roche: Consultancy. Patel:Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; France Foundation: Honoraria. Ridinger:Trovagene: Employment. Silberman:Trovagene: Consultancy. Erlander:Trovagene: Employment. Cortes:Novartis: Consultancy, Research Funding; Arog: Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding.

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Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients

Thrombosis and Haemostasis ◽

10.1055/s-0040-1714214 ◽

2020 ◽

Vol 120 (10) ◽

pp. 1395-1406 ◽

Cited By ~ 1

Author(s):

Iris Garcia-Martínez ◽

Nina Borràs ◽

Marta Martorell ◽

Rafael Parra ◽

Carme Altisent ◽

...

Keyword(s):

Blood Group ◽

Half Life ◽

Robust Regression ◽

Hemophilia A ◽

Illumina Miseq ◽

Activity Levels ◽

Severe Hemophilia ◽

Single Nucleotide Variants ◽

Common Genetic Variants ◽

Recombinant Fviii

AbstractThe pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

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Later sleep timing predicts accelerated summer weight gain among elementary school children: a prospective observational study

International Journal of Behavioral Nutrition and Physical Activity ◽

10.1186/s12966-021-01165-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Jennette P. Moreno ◽

Javad Razjouyan ◽

Houston Lester ◽

Hafza Dadabhoy ◽

Mona Amirmazaheri ◽

...

Keyword(s):

Physical Activity ◽

Observational Study ◽

Sleep Duration ◽

Obesity Prevention ◽

Prospective Observational Study ◽

Light Exposure ◽

Activity Level ◽

Activity Levels ◽

School Year ◽

Children’S Sleep

Abstract Objectives and background Social demands of the school-year and summer environment may affect children’s sleep patterns and circadian rhythms during these periods. The current study examined differences in children’s sleep and circadian-related behaviors during the school-year and summer and explored the association between sleep and circadian parameters and change in body mass index (BMI) during these time periods. Methods This was a prospective observational study with 119 children ages 5 to 8 years with three sequential BMI assessments: early school-year (fall), late school-year (spring), and beginning of the following school-year in Houston, Texas, USA. Sleep midpoint, sleep duration, variability of sleep midpoint, physical activity, and light exposure were estimated using wrist-worn accelerometry during the school-year (fall) and summer. To examine the effect of sleep parameters, physical activity level, and light exposure on change in BMI, growth curve modeling was conducted controlling for age, race, sex, and chronotype. Results Children’s sleep midpoint shifted later by an average of 1.5 h during summer compared to the school-year. After controlling for covariates, later sleep midpoints predicted larger increases in BMI during summer, (γ = .0004, p = .03), but not during the school-year. Sleep duration, sleep midpoint variability, physical activity levels, and sedentary behavior were not associated with change in BMI during the school-year or summer. Females tended to increase their BMI at a faster rate during summer compared to males, γ = .06, p = .049. Greater amounts of outdoor light exposure (γ = −.01, p = .02) predicted smaller increases in school-year BMI. Conclusions Obesity prevention interventions may need to target different behaviors depending on whether children are in or out of school. Promotion of outdoor time during the school-year and earlier sleep times during the summer may be effective obesity prevention strategies during these respective times.

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