Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies

Contains fulltext : 155154.pdf (Publisher’s version ) (Open Access)Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m(2) or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up

Abnormal haemoglobins, Hb Takamatsu and Hb G-Szuhu, detected during the analysis of glycated haemoglobin (HbA(1C)) by high performance liquid chromatography

Background—During medical checkups of two unrelated female outpatients during their annual health examination and one male inpatient suffering from cardiac failure the glycated haemoglobin (HbA(1C)) concentrations measured by high performance liquid chromatography (HPLC) were low, in spite of normal fasting plasma glucose concentrations. However, HbA(1C) concentrations measured by latex immunoagglutination and fructosamine concentrations were within the normal range. Method—Investigations were performed to elucidate the reasons for these discrepancies. Results—Abnormal haemoglobins, Hb Takamatsu and Hb G-Szuhu, were found. The HPLC chromatogram showed an additional peak near HbA(1a+b), which resulted in falsely low HbA(1C) concentrations. Isoelectric focusing analysis of the patients' haemoglobin disclosed abnormal haemoglobins, which migrated faster than normal HbA(1) in the two female patients and slower in the male patient. The cDNA sequence and amino acid analyses of the haemoglobin α-chains and ß-chains indicated the presence of the haemoglobin variant ß 120 Lys→Gln in the two female patients and ß 80 Asn→Lys in the male patient; that is, Hb Takamatsu and Hb G-Szuhu. Conclusions—These cases show how these silent haemoglobin variants can result in falsely low HbA(1C) concentration readings when using HPLC. Key Words: abnormal haemoglobin • high performance liquid chromatography • glycated haemoglobi

Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome

Background Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. Methods We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). Results A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73x10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. Conclusions Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome