Atypical Hemolytic Uremic Syndrome Research Articles

A First-in-Human, Phase 1 Study to Assess the Pharmacodynamic Properties of Single-Dose Iptacopan (CLNP023X2101)

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway (AP). Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Here, we report the exploratory pharmacodynamics of single doses of iptacopan from part 1 of the phase 1 study (CLNP023X2101) in healthy participants. Methods: CLNP023X2101 was a randomized, non-confirmatory, first-in-human assessment of iptacopan in healthy participants. Part 1 was a participant-blinded, placebo-controlled, single-ascending dose (SAD) study. SADs ranged from 5 mg to 400 mg in 56 participants across 7 cohorts. Eight participants per cohort were randomized to receive a single oral dose of iptacopan or placebo in a 3:1 ratio. Inhibition of terminal complex activity of the complement system was assessed using the Wieslab assay which was based on the in vitro formation of the C5b-9 complex, triggered by AP activation. Other soluble biomarkers measured were plasma fragment Bb, a biomarker of AP activation generated by the cleavage of Factor B, and plasma sC5b-9. Results: Demographic data were similar across the treatment groups. Most participants were men with a median age of 45 years. Iptacopan led to dose-dependent suppression of the AP activity as measured by the Wieslab assay ( Figure 1). Following administration, >81% reduction of the AP activity (compared with baseline) was observed at 2 hours post-dose for all dose groups except the 5-mg dose group. Duration of sustained inhibition of AP activity was dose-dependent. Greater than 80% inhibition of the AP activity compared with baseline was maintained beyond 12 hours after 200-mg and 400-mg doses. Wieslab values returned to baseline levels after 48 hours post dose except for the 200-mg and 400-mg cohorts. The decrease in Bb levels from baseline was observed at 2 hours post-dose in all groups and was sustained until 12 hours post-dose before returning to baseline levels by 48 hours ( Figure 2). In the 200-mg and 400-mg cohorts, Bb levels plateaued until 24 hours post-dose and similarly returned to baseline by 48 hours. In contrast, no significant change in Bb level was seen in participants receiving placebo. A trend to decreased sC5b-9 levels was observed until 6 hours post-dose in most cohorts (≥25 mg). Conclusions: Iptacopan achieved rapid, substantial, and sustained dose-dependent suppression of AP activity at 2 hours post-dose for all doses >5 mg. Further validating this result, the decrease in Bb levels at 2 hours post-dose was maintained until 12 hours post-dose, with doses ≥100 mg showing sustained inhibition beyond 12 hours. These pharmacodynamic findings of single-dose iptacopan were part of the rationale for dose selection in clinical Phase 2 and 3 studies contributing to the evidence of 200 mg twice daily being the appropriate dose.

A Phase 1 Study to Assess the Effect of Supratherapeutic Doses of Iptacopan on Cardiac Conduction Parameters and Safety

Introduction: Iptacopan is a first-in-class, oral, selective inhibitor of factor B, a key component of the complement system alternative pathway. Inhibition of the complement system represents a potential mechanism for treatment of several diseases including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. The purpose of this randomized, participant-blinded, placebo-controlled phase 1 study was to assess the effect of supratherapeutic doses on the exposure-response relationship of iptacopan concentration and cardiac conduction, and to assess the cardiac safety and tolerability of ascending, supra-therapeutic single doses of iptacopan. Methods: Supratherapeutic doses of iptacopan 400, 800, and 1200 mg were included in this study, representing ≤6-fold higher dose than the planned clinical dose of 200 mg. The primary endpoints were change from baseline in Fridericia-corrected QT interval (QTcF) and safety endpoints. The analyses included data from this study pooled with part 1 data (single dose) from the first-in-human (CLNP023X2101) study (n=86). The study population included healthy men and women aged 18-55 years. The relationship between iptacopan plasma concentration and change from baseline in QTcF was estimated using a linear mixed effects model. Results: Thirty-two patients were randomized and received placebo (n=8) or iptacopan (n=24). The median age of participants in the 400-mg, 800-mg, 1200-mg, and placebo groups was 51.5, 35, 36, and 37 years, respectively. The upper bound of the 2-sided 90% CI for linear mixed effects model-derived placebo-adjusted change from baseline in QTcF at the geometric mean C max was 2.82 ms for 400-mg, 2.94 ms for 800-mg, and 3.22 ms for 1200-mg doses. Hence, there was no evidence of clinically meaningful QTc prolongation ( Table). The exposure-response analysis of PR and QRS intervals showed no iptacopan concentration-related effects. While the pre-specified and more simple exposure-response analysis of heart rate using change from day 1 baseline (0 hour) revealed an increase of 3 to 5 beats per minute, in a post hoc analysis using 24-hour, time-matched comparison for each participant at each time point before and after study treatment (the more common and gold-standard analysis), iptacopan had no effect on heart rate. No deaths, no moderate or severe treatment-emergent adverse events, and no treatment cohort discontinuations due to adverse events were reported. Conclusions: Three supratherapeutic doses were well tolerated and were not associated with any relevant change in QTcF. Iptacopan did not affect PR or QRS intervals and a time-matched post hoc analysis showed no effect on heart rate. These results indicate that the anticipated clinical dose of iptacopan (200 mg twice daily) has no adverse clinical effects on cardiac function.

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Treatment Patterns Associated with Readmission after Index Hospitalization

Introduction Atypical hemolytic uremic syndrome (aHUS) is associated with dysregulation of the alternative complement pathway and causes significant morbidity and mortality when undiagnosed or inappropriately treated. C5 inhibitors (C5i) improve thrombotic microangiopathy (TMA) response and renal recovery, but significant morbidity may remain. This study described the clinical characteristics and treatment patterns associated with readmission after index hospitalization using real-world evidence from one of the largest, most diverse cohorts of presumed incident aHUS in the United States (US). Methods This was a retrospective cohort study of 634 incident cases among hospitalized adult patients with presumed aHUS derived from the US Premier Healthcare Database, an electronic healthcare records database that contains ~25% of all US hospitalizations (January 1, 2011-June 30, 2021). aHUS was defined as the presence of an International Classification of Diseases (ICD)-9-CM/ICD-10-CM diagnostic code for TMA (446.6, M31.1, M31.10, M31.19) or HUS (283.11, D59.3) and a treatment code (standard charge, HCPCS, ICD-10-PCS) for a C5i, in the absence of a diagnostic code for secondary causes of TMA/HUS or other C5i indications. The proportion of patients readmitted following the index hospitalization was assessed at 30 days and 365 days following discharge, among other timepoints. The time from index hospitalization discharge to all-cause hospital readmission was defined as the number of days from the discharge date of the index hospitalization to the date of all-cause readmission. Readmission for aHUS was defined as a hospitalization lasting ≥2 days to avoid the inclusion of in-hospital infusion clinic visits for C5i treatment. Demographic and clinical characteristics were analyzed using a t-test, Wilcoxon rank test, Fisher's exact test, or Chi-squared test, as appropriate. Results Overall, 78/634 patients (12.3%) died during index hospitalization. Among the 556 patients who survived until discharge, 23.4% and 39.7% had a readmission within 30 days and 365 days, respectively. During the first 365 days, 20.1% of patients required multiple hospitalizations. The median time to first readmission was 27.5 days (interquartile range [IQR]: 9-102 days). Infection was a common cause of readmission (25.6%). Readmission within either 30 or 365 days was associated with longer median time between index admission and therapeutic plasmapheresis (TPE) (3 vs 2 days, p=0.0002, and 3 vs 2 days, p<0.0001, respectively), longer median time between index admission and C5i (10 vs 8 days, p=0.0441, and 10 vs 8 days, p=0.0005, respectively), and longer median time between index admission and renal replacement therapy (RRT; 4 vs 2 days, p=0.0030, and 3 vs 2 days, p=0.0053, respectively). Only readmission within 365 days was associated with median age (52 vs 46 years of age, p=0.0124) or a history of hypertension (80.5% vs 64.5%, p<0.0001), atrial fibrillation (9.5% vs 4.8%, p=0.0363), or heart failure (21.7% vs 14.6%, p=0.0395) at index hospitalization. Readmission within 30 or 365 days was not associated with sex, race, ethnicity, insurance type, geographical region, hospital size or location (rural vs urban), diabetes, chronic kidney disease, myocardial infarction history, TPE, TPE duration, corticosteroids (CS), CS duration, time to CS, RRT requirement, or TMA remission at discharge. Conclusions aHUS readmission rates remain high, despite treatment with C5i, and infection is a common cause of readmission. Delayed TPE, RRT, and C5i treatment for aHUS during index hospitalization, even if only for 1-2 days, were associated with increased readmission within 30 and 365 days. Future efforts should be made to examine the causal relationship between treatment delays and outcomes.

Clinical case of recurrent aHUS after allogeneic cadaveric kidney transplantation

Introduction. Atypical hemolytic uremic syndrome (aHUS) is a systemic orphan disease that reproduces as an uncontrolled activation of the alternative pathway of the complement system and is expressed as systemic thrombotic microangiopathy (TMA). The classical triad of aHUS symptoms are hemolytic anemia, thrombocytopenia, and acute kidney injury (AKI). Currently, diagnosis of aHUS is a diagnosis of exclusion and has no pathognomonic features. It is established based on the clinical presentation of the disease after excluding other forms of TMA, Objective: to increase physicians’ awareness of this rare disease, the diagnosis and treatment of aHUS using a clinical case study.Conclusion. Early diagnosis of aHUS is extremely important, as timely targeted therapy can significantly improve or completely restore the functions of the affected organ.

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Outcomes During Index Hospitalization Diagnosis in the Era of C5 Inhibitor Therapy (C5i)

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Outcomes During Index Hospitalization Diagnosis in the Era of C5 Inhibitor Therapy (C5i)

Atypical Hemolytic Uremic Syndrome with Normal Complement Studies in a Patient with Complement Factor I Deficiency

Atypical Hemolytic Uremic Syndrome with Normal Complement Studies in a Patient with Complement Factor I Deficiency

Anti-Complement Factor H Autoantibodies of the IgM Class and Atypical Hemolytic Uremic Syndrome (aHUS)

Anti-Complement Factor H Autoantibodies of the IgM Class and Atypical Hemolytic Uremic Syndrome (aHUS)

Use of Anti-C5 Inhibitor Leading to Renal Recovery in Combined Typical and Atypical Hemolytic Uremic Syndrome (HUS)

Use of Anti-C5 Inhibitor Leading to Renal Recovery in Combined Typical and Atypical Hemolytic Uremic Syndrome (HUS)

Lupus Nephritis Complicated by Atypical Hemolytic Uremic Syndrome and Heterozygous Deletion in CFHR1-CFHR3 Successfully Treated with Ravulizumab

Lupus Nephritis Complicated by Atypical Hemolytic Uremic Syndrome and Heterozygous Deletion in CFHR1-CFHR3 Successfully Treated with Ravulizumab

Outcome of Kidney Transplantation in Atypical Hemolytic Uremic Syndrome (aHUS): Eculizumab Prophylaxis vs. Rescue Therapy

Outcome of Kidney Transplantation in Atypical Hemolytic Uremic Syndrome (aHUS): Eculizumab Prophylaxis vs. Rescue Therapy

Atypical Hemolytic Uremic Syndrome (aHUS)/TMA in Genetically Predisposed Patients Treated with a Novel Agent for Relapsed/ Refractory Multiple Myeloma

Atypical Hemolytic Uremic Syndrome (aHUS)/TMA in Genetically Predisposed Patients Treated with a Novel Agent for Relapsed/ Refractory Multiple Myeloma

Hospital at Home meets need for new dialysis patients.

The COVID-19 pandemic has had lingering effects in healthcare. During the pandemic, inpatient bed shortages became a major barrier to providing care, and access to outpatient dialysis was delayed due to a shortage of staff. This resulted in lengthy admissions to the hospital while awaiting outpatient dialysis placement in a time when hospital bedspace was a scarce resource. In this report we describe the use of the Hospital at Home program for inpatient dialysis care as a novel method to both provide high quality patient care at home and also open inpatient beds in the hospital. Here, we present two cases where this program served both the needs of the patient and the hospital system by providing dialysis care to patients participating in the Hospital at Home program. One was a patient with a recent kidney transplant awaiting improvement in kidney function following transplant. The other was a new mother who was diagnosed with atypical hemolytic uremic syndrome and was awaiting recovery from her acute kidney injury after receiving complement inhibitor therapy. This program has been functional for the past 13 months and has served 37 patients and saved 1,007 inpatient days during that period. Each inpatient day provided by Hospital at Home represents bed space that was made available to another patient in need.

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Treatment Patterns Associated with Mortality During Index Hospitalization

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics and Treatment Patterns Associated with Mortality During Index Hospitalization

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics Associated with Renal Replacement Therapy (RRT) Initiation During Index Hospitalization and RRT Requirement After Discharge

Atypical Hemolytic Uremic Syndrome (aHUS) Clinical Characteristics Associated with Renal Replacement Therapy (RRT) Initiation During Index Hospitalization and RRT Requirement After Discharge

Atypical Hemolytic Uremic Syndrome from Recent HIV Diagnosis

Atypical Hemolytic Uremic Syndrome from Recent HIV Diagnosis

Experience with Ravulizumab in Atypical Hemolytic Uremic Syndrome

Experience with Ravulizumab in Atypical Hemolytic Uremic Syndrome

An Unusual Case of Lupus-Associated Atypical Hemolytic Uremic Syndrome Presenting with Diffuse Alveolar Hemorrhage and Acute Renal Failure

An Unusual Case of Lupus-Associated Atypical Hemolytic Uremic Syndrome Presenting with Diffuse Alveolar Hemorrhage and Acute Renal Failure

Post-Transplant Thrombotic Microangiopathy as a Manifestation of Atypical Haemolytic Uraemic Syndrome of Primary Origin

Post-Transplant Thrombotic Microangiopathy as a Manifestation of Atypical Haemolytic Uraemic Syndrome of Primary Origin

Atypical Hemolytic Uremic Syndrome Induced by Inflammatory Bowel Disease

Atypical Hemolytic Uremic Syndrome Induced by Inflammatory Bowel Disease

Identification of Patients with Potential Undiagnosed Atypical Hemolytic Uremic Syndrome (aHUS) in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry

Identification of Patients with Potential Undiagnosed Atypical Hemolytic Uremic Syndrome (aHUS) in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry