Danicopan 50mg tablets

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, life-threatening hematologic disorder characterized by chronic hemolysis, bone marrow and organ failure, and thrombotic events. Without effective treatment, PNH can lead to severe complications, including organ damage, increased morbidity, and heightened mortality risk. The high expense and therapeutic revolution that has emerged in PNH necessitates a careful appraisal of its cost-effectiveness. This study aimed to systematically review the cost-effectiveness of disease-modifying therapies (DMTs) in PNH. A comprehensive search syntax was developed to identify relevant studies using online databases. Criteria used in health economic evaluations include costs, effectiveness assessment with life-years gained (LYG) or quality-adjusted life-years (QALY), incremental cost-effectiveness ratio (ICER), and other clinico-economic outcomes. To enable comparison across different countries, the results of economic evaluations allow for the comparison of costs and ICERs across all studies, which were converted into United States Dollars (USD) values using the time model developed. The quality of the studies was assessed using the Quality of Health Economic Studies (QHES) instrument. This study is conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Nine papers were included in the 351 screened records. Pegcetacoplan was a dominant (i.e., less costly and more effective) option compared to C5 complement inhibitors and iptacopan. Eculizumab was not cost-effective compared with other DMTs or the standard of care. The current annual price of $12,300-$13,100 for adding danicopan to ravulizumab was not cost-effective compared to ravulizumab alone. The results of nine studies indicated that the majority of costs are related to the DMTs themselves. The cost-effectiveness analyses of DMTs in PNH suggest that the newer options, pegcetacoplan and iptacopan, are cost-effective and provide greater clinical utility than complement C5 inhibitors, especially eculizumab.

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In 2024, the National Institute for Health and Care Excellence (NICE) recommended two new health technologies for paroxysmal nocturnal haemoglobinuria. This review systematically compares the clinical and cost-effectiveness evidence considered within the NICE single technology appraisals of iptacopan, danicopan and pegcetacoplan, examines the consistency of the clinical evidence and economic modelling, and considers whether single technology appraisals are a suitable apparatus for consistent decision making. The studies used different follow-up lengths and used different definitions for reporting breakthrough haemolysis (BTH), but otherwise reported similar outcomes and found a significant benefit for their interventions. A lack of direct evidence and unreliable indirect comparisons meant that naïve comparisons across trials were carried into the economic modelling despite differences in their control arms. Approaches to modelling BTH and associated dose escalation differed across appraisals, despite information for pegcetacoplan coming from the same source in each appraisal, which had a large impact on the economic results. This review raises the question of whether NICE should implement multiple technology appraisals more frequently to reduce these inconsistences. Additionally, we recommend the development of a framework for revisiting positive recommendations when the implementation of health technologies deviates from assumptions made in the economic modelling to ensure cost-effective healthcare is preserved.

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Objective: This analysis aimed to provide a mechanistic understanding and an evaluation of the clinical relevance of pharmacokinetic drug-drug interactions (DDIs) associated with drugs approved by the Food and Drug Administration in 2024. Methods: , and clinical data. Results: As objects, 11 drugs were identified as clinical substrates. Of these, 7 drugs were substrates of CYP3A, 3 of CYP2C9, one of CYP1A2, and one of CYP2C8, including the sensitive substrates vanzacaftor (CYP3A) and vorasidenib (CYP1A2). As precipitants, 6 drugs (acoramidis, cefepime/enmetazobactam, givinostat, lazertinib, mavorixafor, and resmetirom) were clinical inhibitors of CYP enzymes (2C8, 2C9, 2D6, 2E1, and 3A), with mavorixafor being a CYP2D6 strong inhibitor. Two drugs (elafibranor and tovorafenib) showed weak induction of CYP3A. Regarding transporter data, 3 drugs were substrates of transporters, including seladelpar (BCRP and OAT3), sulopenem (OAT3), and vadadustat (OAT1/3), and 8 drugs (arimoclomol, danicopan, givinostat, lazertinib, mavorixafor, resmetirom, vadadustat, and vazacaftor/tezacaftor/deutivacaftor) were inhibitors of transporters. All clinical DDIs with AUC changes ≥ 2-fold triggered labeling recommendations. Several DDIs with an AUC change <2 also had labeling recommendations, pertaining most often to the concomitant use of drugs with a narrow therapeutic index. Conclusions: Mechanistic DDI insights from newly approved therapies can be extrapolated to inform the management of commonly co-administered drugs, supporting a safer and more effective use of new drug products in the context of polypharmacy.

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Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D inhibitor. Therapeutic factor D inhibition was designed to control intravascular hemolysis and prevent C3-mediated extravascular hemolysis. In this open-label, phase II, dose-finding trial, ten untreated PNH patients with hemolysis received danicopan monotherapy (100-200 mg thrice daily). Endpoints included changes in the concentrations of lactate dehydrogenase (LDH) at day 28 (primary endpoint), of LDH at day 84, and of hemoglobin. Safety, pharmacokinetics/ pharmacodynamics, and patient-reported outcomes were assessed. Ten patients reached the primary endpoint; two later discontinued treatment: one because of 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. Intravascular hemolysis was inhibited, as demonstrated by a mean decrease of LDH (5.7 times upper limit of normal [ULN] at baseline vs. 1.8 times ULN at day 28 and 2.2 times ULN at day 84; both P&lt;0.001). Mean baseline hemoglobin, 9.8 g/dL, increased by 1.1 (day 28) and 1.7 (day 84) g/dL (both P&lt;0.005). No significant C3 fragment deposition occurred on glycosylphosphatidylinositol- deficient erythrocytes. Mean baseline Functional Assessment of Chronic Illness Therapy–Fatigue score, 34, increased by 9 (day 28) and 13 (day 84) points. The most common adverse events were headache and upper respiratory tract infection. These phase II, monotherapy data show that proximal inhibition with danicopan provides clinically meaningful inhibition of intravascular hemolysis and increases hemoglobin concentration in untreated PNH patients, without evidence of C3-mediated extravascular hemolysis. This trial was registered at www.clinicaltrials.gov (#NCT03053102).

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ABSTRACT: Complement C5 inhibitor treatment with ravulizumab or eculizumab for paroxysmal nocturnal hemoglobinuria (PNH) improves outcomes and survival. Some patients remain anemic due to clinically significant extravascular hemolysis (cs-EVH; hemoglobin [Hb] ≤9.5 g/dL and absolute reticulocyte count [ARC] ≥120 × 109/L). In the phase 3 ALPHA trial, participants received oral factor D inhibitor danicopan (150 mg 3 times daily) or placebo plus ravulizumab or eculizumab during the 12-week, double-blind treatment period 1 (TP1); those receiving placebo switched to danicopan during the subsequent 12-week, open-label TP2 and continued during the 2-year long-term extension (LTE). There were 86 participants randomized in the study, of whom 82 entered TP2, and 80 entered LTE. The primary end point was met, with Hb improvements from baseline at week 12 (least squares mean change, 2.8 g/dL) with danicopan. For participants switching from placebo to danicopan at week 12, improvements in mean Hb were observed at week 24. Similar trends were observed for the proportion of participants with ≥2 g/dL Hb increase, ARC, proportion of participants achieving transfusion avoidance, and Functional Assessment of Chronic Illness Therapy-Fatigue scale scores. Improvements were maintained up to week 72. No new safety signals were observed. The breakthrough hemolysis rate was 6 events per 100 patient-years. These long-term data demonstrate sustained efficacy and safety of danicopan plus ravulizumab/eculizumab for continued control of terminal complement activity, intravascular hemolysis, and cs-EVH in PNH. This trial was registered at www.clinicaltrials.gov as #NCT04469465.

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INTRODUCTION: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). METHODS: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. RESULTS: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. CONCLUSION: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.

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