scholarly journals A Phase 2 Trial of the Protein C Activator AB002 in End-Stage Renal Disease Patients on Chronic Hemodialysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 669-669
Author(s):  
Norah G Verbout ◽  
Christina U Lorentz ◽  
Brandon D Markway ◽  
Michael Wallisch ◽  
Joseph J Shatzel ◽  
...  
Keyword(s):  
End Stage Renal Disease ◽  
Protein C ◽  
Drug Exposure ◽  
Bleeding Risk ◽  
Chronic Hemodialysis ◽  
Phase 2 ◽  
Stage Renal Disease ◽  
End Stage ◽  
Dose Levels ◽  
Esrd Patients

Abstract Background: During hemodialysis of patients with renal failure, thrombi that form within the dialyzer circuit cause blood entrapment, blood loss, reduced dialysis efficiency and may require dialyzer changeouts. Anticoagulation with heparin is effective in preventing clot formation within the circuit, but is contraindicated in a subset of end-stage renal disease (ESRD) patients on chronic hemodialysis due to bleeding risk or heparin intolerance. A safe, short-acting alternative to heparin is an unmet need for this patient population, and for others suffering from or at risk of thrombosis. AB002 is a first-in-class protein C activator thrombin analog that targets to the thrombus interface and generates endogenous activated protein C (APC) without cleaving prothrombotic substrates. In a preclinical baboon thrombosis model, AB002 rapidly interrupted thrombus development with no observable hemostasis impairment, and was similar in antithrombotic efficacy to high-dose enoxaparin while appearing superior to interventional tissue-plasminogen activator. This proof-of-concept phase 2 clinical trial was designed to evaluate the safety, tolerability, efficacy, and pharmacodynamics of AB002 as a heparin alternative for ESRD patients. Methods: In this phase 2, randomized, double-blind, placebo-controlled study, a single dose of AB002 (1.5 µg/kg or 3 µg/kg) or placebo was infused into the hemodialysis line over four hours in 36 ESRD patients undergoing heparin-free hemodialysis (NCT03963895). Patients underwent five sequential heparin-free hemodialysis sessions over a period of 10 days, with three occurring prior to dosing, one on the day of dosing, and one after dosing. A total of 179 hemodialysis sessions were evaluated. Safety parameters were recorded throughout the study and immunogenicity to AB002 or thrombin was monitored by validated assays. Clotting within the dialyzer circuit was visually assessed and the number of occlusive events requiring a changeout of the circuit recorded. Circulating plasma APC-protein C inhibitor complexes (APC-PCI) and thrombin-antithrombin (TAT) complexes, markers of drug exposure and thrombin generation, respectively, were quantified by ELISA. This study was approved by the local ethics review board and all patients provided informed consent. Results: AB002 demonstrated a favorable safety profile, with no treatment-related adverse events. Clinically relevant bleeding did not occur in any patient and the time to hemostasis at the vascular access site was not affected by AB002. There was no evidence of AB002-induced anti-drug or anti-thrombin antibodies at 14 days post-dose. The frequency of occlusive events requiring circuit changeouts was 13.9% (21/155) on days in which AB002 was not administered, compared to 0% (0/12) and 8.3% (1/12) at the 1.5 µg/kg and 3 µg/kg dose levels, respectively. Compared to placebo, the incidence of high-grade clotting in the hemodialyzer decreased by 49% and 62% at the 1.5 µg/kg and 3 µg/kg AB002 dose levels, respectively. Hemodialysis increased TAT levels measured at the end of hemodialysis approximately 12-fold over baseline in patients given placebo. By contrast, AB002 attenuated TAT generation to 4-fold and 2-fold over baseline at the 1.5 µg/kg and 3 µg/kg dose levels, respectively. Hemodialysis-induced TAT generation was not different across groups on non-dosing days. Drug exposure was confirmed by a transient, dose-dependent elevation of circulating APC-PCI complexes following AB002 administration. Conclusions: In ESRD patients undergoing heparin-free hemodialysis, AB002 was well-tolerated and reduced thrombus accumulation in the hemodialysis circuit without observable hemostasis impairment. The results of this study support further clinical evaluation of AB002 as a novel drug candidate to limit thrombus development or device-initiated clotting in patients with elevated bleeding risk, including ESRD patients on chronic heparin-free hemodialysis. Disclosures Verbout: Aronora, Inc.: Current Employment. Lorentz: Aronora, Inc.: Current Employment. Markway: Aronora, Inc.: Current Employment. Wallisch: Aronora Inc,: Current Employment. Shatzel: Aronora Inc,: Consultancy. Gruber: Aronora Inc.: Current Employment, Current equity holder in publicly-traded company; Oregon Health and Science University: Current Employment.

scholarly journals Safety and Antithrombotic Efficacy of the Recombinant Protein C Activator AB002 (E-WE Thrombin) in End Stage Renal Disease Patients on Chronic Hemodialysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2433-2433
Author(s):  
Norah G Verbout ◽  
Christina U Lorentz ◽  
Brandon D Markway ◽  
Joseph J Shatzel ◽  
Erik I Tucker ◽  
...  
Keyword(s):  
End Stage Renal Disease ◽  
Protein C ◽  
Activated Protein C ◽  
Phase 2 ◽  
Employment Equity ◽  
Equity Ownership ◽  
Stage Renal Disease ◽  
End Stage ◽  
Dose Levels ◽  
Esrd Patients

AB002 is a recombinant thrombin analog that generates endogenous activated protein C (APC) on intravascular surfaces in a thrombomodulin-dependent manner but does not promote thrombosis. Endogenously generated APC downregulates thrombin generation, thereby reducing pathological clot formation. During hemodialysis (HD), thrombi can form within the dialyzer filter and circuit, reducing dialyzer efficiency, and increasing blood loss. Heparin administration reduces clotting within the filter and circuit, but increases bleeding risk and is not tolerated in all patients. Since end-stage renal disease (ESRD) patients undergoing HD are at higher risk of both thromboembolism and bleeding, a safe, short-term and self-limiting anticoagulant alternative to heparin is currently an unmet need for this population. This is a phase 2, randomized, double-blind, placebo-controlled, single-dose study designed to evaluate the safety and efficacy of AB002 at two dose levels when administered to ESRD patients during heparin-free HD. A total of 36 adult patients are planned to be enrolled into two cohorts and dosed sequentially. Within each cohort, patients will be randomized to active drug (12) or placebo (6). Dose levels (1.5 µg/kg or 3 µg/kg; iv infusion) were based on safety data from a completed phase 1 study performed in healthy adult subjects (NCT03453060), which demonstrated that a single dose of AB002 was well tolerated, as well as based on preclinical efficacy studies performed in a baboon vascular thrombosis model. The primary objective of this phase 2 proof-of-concept study is safety and tolerability assessed as the number and severity of adverse events (AE), changes in baseline physical and lab parameters and immunogenicity of AB002. The number and severity of AE will be tabulated and summary statistics evaluated. The secondary objectives are to assess 1) pharmacodynamics using activated protein C/protein C inhibitor complexes in plasma as a surrogate marker for drug exposure, and 2) efficacy via pre-post dialyzer pressures, visual inspection of thrombus accumulation in the HD filter and dialysis efficiency based on urea kinetics. The study population includes ESRD patients on a stable outpatient HD regimen at least 3 times per week and excludes patients with history of acute vaso-occlusive thrombotic events, concomitant use of anticoagulant/antiplatelet agents immediately prior to and during the study, active cancer and bleeding disorders. This study is currently recruiting participants at one study site (Orlando Clinical Research Center) in Orlando, FL and is estimated to complete in October 2020 (NCT03963895). Disclosures Verbout: Aronora, Inc.: Employment, Equity Ownership. Lorentz:Aronora, Inc.: Employment. Markway:Aronora, Inc.: Employment. Shatzel:Aronora, Inc.: Consultancy. Tucker:Aronora, Inc.: Employment, Equity Ownership. Gruber:Aronora, Inc.: Employment, Equity Ownership.

Safety and Efficacy of the Contact Activation Inhibitor AB023 in Patients with End-Stage Renal Disease on Chronic Hemodialysis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Christina U Lorentz ◽  
Norah G Verbout ◽  
Joseph J Shatzel ◽  
Michael Wallisch ◽  
Brandon D Markway ◽  
...  
Keyword(s):  
Chronic Hemodialysis ◽  
Contact System ◽  
Clot Formation ◽  
Phase 2 ◽  
Access Site ◽  
Post Dose ◽  
Double Blind ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Background: End stage renal disease (ESRD) patients on chronic hemodialysis (HD) repeatedly have their blood exposed to artificial surfaces within the hemodialysis circuit, which triggers contact system-initiated coagulation. Clot formation within the HD circuit results in blood loss, decreased HD efficiency, and device circuit failure. Heparin reduces circuit clotting but it is not tolerated by all patients. Mounting experimental data suggest that contact system inhibition is antithrombotic without significantly compromising hemostasis. AB023 is a unique recombinant anti-factor (F) XI antibody that interferes with the interactions of FXI and FXII without inhibiting FXI activation by thrombin or the activation of FIX by activated FXI. This study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of AB023 in patients with ESRD on chronic HD. Methods: In this phase 2, randomized, double-blind, placebo-controlled, single-administration study, AB023 (0.25 or 0.5 mg/kg) or placebo was injected into the HD circuit of 24 ESRD patients at the start of heparin-free HD (NCT03612856). All patients underwent three pre-dose HD procedures and four monitored post-dose HD sessions. In total, the study encompassed 168 individual HD sessions, 72 of which occurred pre-dose and 96 of which occurred post-dose. Safety parameters, including time to hemostasis at HD access site, prothrombin time, physical examinations, vital signs, electrocardiograms, clinical chemistry, immunogenicity and other adverse events (AEs), were recorded. Clotting within the hemodialyzer circuit was assessed using a visual clotting scale by investigators who were blinded to treatment. The frequency of circuit clot obstructions requiring dialyzer exchange was also recorded. Pharmacokinetic and pharmacodynamic parameters, including activated partial thromboplastin times, were also assessed. The study was approved by an ethics review board and all subjects provided written informed consent. Results: AB023 demonstrated a favorable safety profile in ESRD patients. No drug-related AEs were noted. Clinically relevant bleeding did not occur in any patient, and the time to hemostasis at the HD access site was unchanged after AB023 administration. As expected, the aPTT was prolonged after AB023 administration, reaching saturation at both dose levels (about 2-fold prolongation) immediately after dosing, and remaining prolonged for up to 9 days with the high dose. Compared with pretreatment, the frequency of occlusive events requiring circuit exchange decreased by 68% and 50% in subjects given the 0.25 and 0.5 mg/kg AB023 respectively, while the number of occlusive events was numerically unchanged in the placebo arm. Likewise, the number of saline flushes required to maintain circuit patency decreased by 44% and 85%, and the incidence of high-grade clotting in the hemodialyzer as assessed by visual scoring decreased by 15% and 43% on day 1, 8% and 35% by day 3, and 0% and 19% by day 5 in the 0.25 and 0.5 mg/kg cohorts, respectively. Conclusions: Anticoagulation with AB023 was well-tolerated and reduced clot formation within the HD circuit of ESRD patients. These findings suggest that inhibiting contact system activation could reduce medical device-initiated blood clot formation in patients. Disclosures Lorentz: Aronora, Inc.: Current Employment. Verbout:Aronora, Inc.: Current Employment. Shatzel:Aronora, Inc.: Consultancy. Wallisch:Aronora, Inc.: Current Employment. Markway:Aronora, Inc.: Current Employment. Tucker:Aronora, Inc.: Current Employment. Gruber:Aronora, Inc.: Current Employment, Current equity holder in private company.

Treatment with Cinacalcet in Hemodialysis Patients with Severe Secondary Hyperparathyroidism, Influences Bone Mineral Metabolism and Anemia Parameters

2020 ◽  
Vol 15 (3) ◽  
pp. 249-263
Author(s):  
Maria Aktsiali ◽  
Theodora Papachrysanthou ◽  
Ioannis Griveas ◽  
Christos Andriopoulos ◽  
Panagiotis Sitaras ◽  
...  
Keyword(s):  
Bone Mineral ◽  
Mineral Metabolism ◽  
Treatment Options ◽  
Dry Weight ◽  
Chronic Hemodialysis ◽  
Protective Agent ◽  
Positive Correlation ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Background: Due to the premium rate of Chronic Kidney Disease, we have increased our knowledge with respect to diagnosis and treatment of Bone Mineral Disease (BMD) in End- Stage Renal Disease (ESRD). Currently, various treatment options are available. The medication used for Secondary Hyper-Parathyroidism gives promising results in the regulation of Ca, P and Parathormone levels, improving the quality of life. The aim of the present study was to investigate the relation of cinacalcet administration to not only parathormone, Ca and P but also to anemia parameters such as hematocrit and hemoglobin. Materials and Methods: retrospective observational study was conducted in a Chronic Hemodialysis Unit. One-hundred ESRD patients were recruited for twenty-four months and were evaluated on a monthly rate. Biochemical parameters were related to medication prescribed and the prognostic value was estimated. Cinacalcet was administered to 43 out of 100 patients in a dose of 30-120 mg. Results: Significant differences were observed in PTH, Ca and P levels with respect to Cinacalcet administration. Ca levels appeared to be higher at 30mg as compared to 60mg cinacalcet. Furthermore, a decreasing age-dependent pattern was observed with respect to cinacalcet dosage. A positive correlation was observed between Dry Weight (DW) and cinacalcet dose. Finally, a positive correlation between Hematocrit and Hemoglobin and cinacalcet was manifested. Conclusions: Cinacalcet, is a potential cardiovascular and bone protective agent, which is approved for use in ESRD patients to assist SHPT. A novel information was obtained from this study, regarding the improvement of the control of anemia.

Iron Chelation Therapy in CAPD: A New and Effective Treatment of Iron Overload Disease in Esrd Patients

1983 ◽  
Vol 3 (2) ◽  
pp. 99-101 ◽  
Author(s):  
Glen H Stanbaugh ◽  
A. W, Holmes Diane Gillit ◽  
George W. Reichel ◽  
Mark Stranz
Keyword(s):  
Peritoneal Dialysis ◽  
Iron Overload ◽  
End Stage Renal Disease ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelation Therapy ◽  
Peritoneal Dialysate ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

A patient with end-stage renal disease on CAPD, and with massive iron overload is reported. This patient had evidence of myocardial and hepatic damage probably as a result of iron overload. Treatment with desferoxamine resulted in removal of iron in the peritoneal dialysate. On the basis of preliminary studies in this patient it would appear that removal of iron by peritoneal dialysis in conjunction with chelation therapy is safe and effective. This finding should have wide-ranging signficance for patients with ESRD.

Adipokines and Gut Hormones in End-Stage Renal Disease

2007 ◽  
Vol 27 (2_suppl) ◽  
pp. 298-302
Author(s):  
Robert H. Mak ◽  
Wai Cheung
Keyword(s):  
Renal Disease ◽  
End Stage Renal Disease ◽  
Peptide Yy ◽  
Gut Hormones ◽  
Poor Quality ◽  
Mortality And Morbidity ◽  
Novel Therapeutic Strategies ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Cachexia is common in end-stage renal disease (ESRD) patients, and it is an important risk factor for poor quality of life and increased mortality and morbidity. Chronic inflammation is an important cause of cachexia in ESRD patients. In the present review, we examine recent evidence suggesting that adipokines or adipocytokines such as leptin, adiponectin, resistin, tumor necrosis factor α, interleukin-6, and interleukin-1β may play important roles in uremic cachexia. We also review the physiology and the potential roles of gut hormones, including ghrelin, peptide YY, and cholecystokinin in ESRD. Understanding the molecular pathophysiology of these novel hormones in ESRD may lead to novel therapeutic strategies.

scholarly journals Prevalence and Associated Factors of Frailty and Mortality in Patients with End-Stage Renal Disease Undergoing Hemodialysis: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 18 (7) ◽  
pp. 3471
Author(s):  
Hyeon-Ju Lee ◽  
Youn-Jung Son
Keyword(s):  
Systematic Review ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Associated Factors ◽  
Meta Analysis ◽  
Screening Tools ◽  
Cochrane Library ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients

Hemodialysis is the most common type of treatment for end-stage renal disease (ESRD). Frailty is associated with poor outcomes such as higher mortality. ESRD patients have a higher prevalence of frailty. This systematic review and meta-analysis aimed to identify the prevalence and associated factors of frailty and examine whether it is a predictor of mortality among ESRD patients undergoing hemodialysis. Five electronic databases including PubMed, Embase, CINAHL, Web of Science, and Cochrane Library were searched for relevant studies up to 30 November 2020. A total of 752 articles were found, and seven studies with 2604 participants in total were included in the final analysis. The pooled prevalence of frailty in patients with ESRD undergoing hemodialysis was 46% (95% Confidence interval (CI) 34.2−58.3%). Advanced age, female sex, and the presence of diabetes mellitus increased the risk of frailty in ESRD patients undergoing hemodialysis. Our main finding showed that patients with frailty had a greater risk of all-cause mortality compared with those without (hazard ratio (HR): 2.02, 95% CI: 1.65−2.48). To improve ESRD patient outcomes, healthcare professionals need to assess the frailty of older ESRD patients, particularly by considering gender and comorbidities. Comprehensive frailty screening tools for ESRD patients on hemodialysis need to be developed.

Fibrin clot structure in patients with end-stage renal disease

2007 ◽  
Vol 98 (08) ◽  
pp. 339-345 ◽  
Author(s):  
Johannes Sidelmann ◽  
Mikkel Brabrand ◽  
Robert Pedersen ◽  
Jørgen Pedersen ◽  
Kim Esbensen ◽  
...  
Keyword(s):  
Renal Disease ◽  
End Stage Renal Disease ◽  
Healthy Controls ◽  
Structure Characteristics ◽  
Stage Renal Disease ◽  
End Stage ◽  
Esrd Patients ◽  
Fibrin Structure ◽  
Plasma Markers ◽  
Fibrin Clots

SummaryFibrin clots with reduced permeability, increased clot stiffness and reduced fibrinolysis susceptibility may predispose to cardiovascular disease (CVD). Little is known, however, about the structure of fibrin clots in patients with end-stage renal disease (ESRD).These patients suffer from a high risk of CVD in addition to their chronic low-grade inflammation. Using permeability, compaction and turbidity studies in 22 ESRD patients and 24 healthy controls, fibrin clots made from patient plasma were found to be less permeable (p<0.001), less compactable (p<0.001), and less susceptible to fibrinolysis (p<0.001) than clots from controls.The maximum rate of turbidity increase was also higher for the patients than controls (p<0.001), and scan-ning electron microscopy revealed higher clot density of fibrin fibers in clots from patients than clots from controls (p<0.001). Patients had higher plasma concentrations of fibrinogen, C-reative protein and interleukin 6 than controls.These plasma markers of inflammation correlated significantly with most of the fibrin structure characteristics observed in the patients. In contrast, plasma markers of azothemia showed no such correlations. The results suggest that in ESRD patients fibrin clots are significantly different from healthy controls, and that the fibrin structure characteristics in the patients are associated primarily with the inflammatory plasma milieu rather than with level of azothemia.

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