Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Objectives: Although complement inhibition is highly effective, patients with paroxysmal nocturnal hemoglobinuria (PNH) may experience intravascular breakthrough hemolysis (BTH). Underlying causes may include elevated free C5, pregnancy, or non-pregnancy complement-activating conditions (e.g. infections). This study compared BTH-related resource utilization and costs in PNH patients treated with eculizumab versus ravulizumab. Methods: A cost model was developed using data from a targeted literature review and a survey of experienced clinicians. Costs associated with BTH episodes were calculated by cause and weighted by the proportion attributed to each cause and the cost of treating each episode. The model captured direct medical costs in 2018 US dollars. Annual BTH-related healthcare resource utilization was also calculated. Results: BTH episodes in the literature were commonly associated with elevated lactate dehydrogenase and aspartate aminotransferase, hemoglobinuria, transfusion needs, and/or recurrence of PNH symptoms. The majority of BTH management costs in eculizumab-treated patients related to changing from the approved dosing regimen following an episode of BTH, rather than acute management. No ongoing dosing changes were expected for ravulizumab-treated patients following episodes of BTH, substantially reducing its ongoing management costs. Resource utilization was greater for eculizumab-treated patients than ravulizumab-treated patients due to higher incidence of BTH, and risk of elevated free C5-related BTH. Total incremental cost was substantially lower for ravulizumab- vs eculizumab-treated patients ($407 vs $9379); results were consistent when pregnant women were not included ($386 vs $3472). Conclusion: Overall resource use and costs for BTH are estimated to be lower for PNH patients receiving ravulizumab compared with eculizumab.
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PMID:Cost burden of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria receiving ravulizumab versus eculizumab. 3285 39

Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.
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PMID:Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. 3312 Dec 36