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Background: Modulation of glucocorticoid receptor (GR) activity in tumor cells enhances chemotherapy efficacy. We evaluated the selective GR modulator relacorilant plus nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who had received at least 2 prior therapy lines., Patients and Methods: In this open-label, single-arm, phase III study, patients received once-daily oral relacorilant (100 mg, titrated to 150 mg in 25 mg increments/cycle) and nab-paclitaxel (80 mg/m2) on days 1, 8, and 15 of 28-day cycles. The primary efficacy endpoint was objective response rate (ORR) by blinded independent central review. Progression-free survival (PFS), overall survival (OS), target gene modulation, and safety were also assessed., Results: Of 43 patients enrolled, 31 were evaluable for ORR (12 did not reach first postbaseline radiographic assessment). An interim analysis to assess whether ORR was ≥10% showed no confirmed responses and the study was discontinued. Two (6.5%) patients attained unconfirmed partial responses and 15 (48.4%) had stable disease. Fourteen of 31 (45.2%) patients had reductions in target lesion size, despite prior nab-paclitaxel exposure in 12 of the 14. Median PFS and OS were 2.4 months (95% CI, 1.4-4.2) and 3.9 months (95% CI, 2.8-4.9), respectively. The most common adverse events were fatigue and nausea. RNA analysis confirmed that relacorilant plus nab-paclitaxel suppressed 8 cortisol target genes of interest., Conclusion: Relacorilant plus nab-paclitaxel showed modest antitumor activity in heavily pretreated patients with mPDAC, with no new safety signals. Studies of this combination in other indications with a high unmet medical need are ongoing., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: To assess the safety and efficacy of ripasudil for retinopathy of prematurity (ROP)., Study Design: Phase 1/2, multicenter, open-label, single-arm, 12-week clinical trial., Methods: Infants born with gestational age (GA) of ≤ 32 weeks or weight of ≤ 1500 g with zone I or II, ≥ stage 1, ROP in both eyes were enrolled. Ripasudil eye drops were administered to patients in both eyes. Phase 1 was a dose-escalation study (once daily for 1 week, then twice daily for 2 weeks); an additional dosing up to 9 weeks was allowed if no safety issues occurred. In phase 2, ripasudil was administered twice daily for up to 12 weeks. Adverse events were assessed. The proportion of patients with type 1 ROP progression, number of days for type 1 ROP progression, and progression to the most advanced ROP stage were estimated., Results: Twenty-four infants were enrolled (phase 1, n = 3; phase 2, n = 21). Nineteen and four patients experienced systemic and ocular adverse events, respectively. Efficacy endpoints were not different between the ripasudil and historical control groups. However, in the GA ≤ 27 weeks subgroup, fewer patients progressed to type 1 ROP in the ripasudil than in the historical control group (P = 0.09). In the GA ≤ 27 weeks subgroups, the 25th percentile for the number of days for type 1 ROP progression was 22 days in the historical control group and 44 days in the ripasudil group., Conclusion: Ripasudil was safe and inhibited/delayed type 1 ROP progression, especially in infants with short GA., (© 2024. Japanese Ophthalmological Society.)

Purpose: To explore safety and tolerability parameters for the niraparib individualized starting dose (ISD) in patients with newly diagnosed advanced ovarian cancer that responded to platinum-based chemotherapy who participated in the phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016)., Methods: The PRIMA protocol was amended so newly enrolled patients received an ISD based on baseline body weight/platelet count. In this ad hoc analysis, the timing, duration, and resolution of the first occurrence of common any-grade hematologic (thrombocytopenia, anemia, neutropenia) and nonhematologic (nausea, asthenia/fatigue, constipation, insomnia, hypertension) treatment-emergent adverse events (TEAEs) were evaluated by treatment arm in the ISD safety population (data cutoff, November 17, 2021; median follow-up, 3.5 years)., Results: Of 733 randomized patients, 255 were enrolled after the ISD protocol amendment and received ≥ 1 dose of study treatment (niraparib, 169; placebo, 86). In the niraparib arm, median times to first events were 22.0-35.0 days for hematologic TEAEs and 7.0-56.0 days for nonhematologic TEAEs. First events resolved in ≥ 89.8% of patients for hematologic TEAEs; for nonhematologic TEAEs, resolution rates ranged from 55.3% (insomnia) to 86.0% (nausea). Median durations of first hematologic TEAEs were ≤ 16.0 days, but for first nonhematologic TEAEs ranged from 18.0 days (nausea) to 134.0 days (insomnia)., Conclusion: The niraparib ISD was generally well tolerated and TEAEs were manageable. Common hematologic and nonhematologic TEAEs occurred early and first events of hematologic TEAEs had a short duration (≈ 2 weeks) and a high resolution rate. These findings support close monitoring immediately following niraparib initiation and may help inform patient expectations for niraparib safety., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Vulsteke reports medical writing support from GSK; consulting fees from Astellas, Atheneum Partners, Bristol Myers Squibb, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme, and Roche; advisory board fees from AstraZeneca, Bayer, GSK, Janssen-Cilag, Leo Pharma, Merck Sharp & Dohme; and travel support from Pfizer and Roche. Dr Chambers has nothing to disclose. Dr Rubio Pérez has nothing to disclose. Dr Chan reports research, consulting, and speakers' bureau fees from AbbVie, Acerta, Aravive, AstraZeneca, Clovis, Eisai, GSK, Merck, and Roche. Dr Raaschou-Jensen reports advisory board fees from Eisai. Dr Zhuo has nothing to disclose. Dr Lorusso reports consulting fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, MSD, PharmaMar, and Seagen; honoraria from AstraZeneca, Clovis Oncology, GSK, MSD, and PharmaMar; payment for expert testimony from Clovis Oncology; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, PharmaMar, and Roche; personal advisory board fees from AstraZeneca, Clovis Oncology, Corcept, Genmab, GSK, Immunogen, Merck Serono, MSD, Oncoinvent, PharmaMar, Seagen, and Sutro; member of board of directors at GCIG (no compensation); medical writing support from Clovis Oncology, GSK, MSD, and PharmaMar; and institutional funding for work in clinical trials from AstraZeneca, Clovis Oncology, Genmab, GSK, Immunogen, Incyte, MSD, Novartis, PharmaMar, Roche, and Seagen. Dr Herzog reports personal consulting fees from Aadi, AstraZeneca, Caris, Clovis, Eisai, Epsilogen, Genentech, GSK, Immunogen, J&J, Merck, Mersana, and Seagen; participation on a data safety monitoring board or advisory board from Corcept; and leadership role on the GOG Foundation Board and president of GOG Partners. Dr de la Motte Rouge reports consulting fees from AstraZeneca, Clovis Oncology, Eisai, Gilead, GSK, MSD, Novartis, Pfizer, and Sanofi; honoraria from AstraZeneca, GSK, MSD, NetCancer, and Pfizer; and travel support from Gilead, MSD, and Pfizer. Dr Thomes Pepin has nothing to disclose. Dr Braicu reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). Dr Chen reports author royalties from UpToDate and serves on the board of directors of the American College of Obstetricians and Gynecologists, on the board of governors of the American College of Surgeons, and as a board member for the NCI PDQ Cancer Genetics Board. Dr Levy has nothing to disclose. Dr Barter has nothing to disclose. Dr Barretina-Ginesta reports consulting or advisory role fees from AstraZeneca, Clovis Oncology, GSK, MSD, PharmaMar, and Roche; and travel support from AstraZeneca, GSK, MSD, PharmaMar, and Roche. Dr Joosens reports travel fees from MSD. Ms York and Dr Malinowska are current employees of GSK. Dr González-Martín reports fees for different educational or advisory-related activities from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Hedera Dx, Immunogen, Illumina, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, PharmaMar, Regeneron, Roche, Seagen, Sotio, Sutro, Takeda, and Tubulis. Dr Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Roxadustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor, has proven efficacy in the treatment of renal anemia; however, evidence indicates that it may cause central hypothyroidism. The prevalence and reversibility of roxadustat-induced central hypothyroidism in patients undergoing hemodialysis remain unclear. Here, we retrospectively analyzed thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) levels in 51 patients (mean age: 72.3 ± 10.7 years; 58.8% male) undergoing hemodialysis before, during, and after halting roxadustat treatment. TSH levels were significantly decreased from a median of 2.46 (interquartile range:1.60-4.51) mU/L before roxadustat treatment to 1.36 (0.72-2.41) mU/L during treatment ( p  < 0.001), and improved to 2.56 (1.78-4.63) mU/L after halting roxadustat ( p  < 0.001). Similarly, FT4 levels decreased from 1.11 (0.97-1.24) ng/dL before roxadustat treatment to 0.92 (0.71-1.03) ng/dL during treatment ( p  < 0.001) and improved to 1.05 (0.93-1.17) ng/dL after halting roxadustat ( p  < 0.001). FT3 levels were 2.04 (1.78-2.31) pg/mL before starting roxadustat, 1.97 (1.69-2.27) pg/mL during treatment, and 1.90 (1.63-2.18) pg/mL after halting roxadustat, with no significant difference between each group. Moreover, 2.0% of patients exhibited extremely low TSH levels (≤0.1 mU/L) and low TSH levels (>0.1 mU/L to <0.4 mU/L) before starting roxadustat and that percentage increased to 5.9% and 7.8%, respectively, during treatment. After roxadustat cessation, extremely low or low TSH levels recovered in all patients. Taken together, the results indicate that roxadustat can cause reversible central hypothyroidism in patients undergoing hemodialysis.

Background: Hyperphosphatemia occurs universally in end-stage renal disease(ESRD), and the attainment of target serum phosphate levels remains suboptimal with currently available phosphate binders. This meta-analysis aimed to evaluate the efficacy and safety of tenapanor in end-stage renal disease patients with hyperphosphatemia., Methods: Data sources included PubMed, Embase, Web of Science, and Cochrane Library. This meta-analysis included randomized controlled trials evaluating both the efficacy of tenapanor in reducing serum phosphate levels and its safety profile. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs. The GRADE system was used to assess the overall certainty of evidence. A meta-analysis was carried out by using fixed effects ( I 2 values < 50%) or random effects ( I 2 values ≥ 50%) models to calculate MD with 95% CI for continuous outcome variables and RR with 95% CI for dichotomous variables. Publication bias was evaluated using funnel plots., Results: A total of seven RCTs involving 877 individuals were included. The pooling analysis demonstrates that the reduction in mean serum phosphorus levels in the tenapanor group was significantly greater than that in the placebo group [MD= -1.06 mg/dl, 95% CI (-1.59, -0.53); I 2  = 83%, p  < 0.0001]. The proportion of patients achieving a serum phosphorus level of < 5.5 mg/dL, along with the incidence of any adverse events (AEs) and gastrointestinal disorders, was higher in the tenapanor group compared to the placebo group., Conclusion: Tenapanor has the potential to significantly reduce serum phosphorus levels and enhance the rate of achieving target levels compared to placebo, all while maintaining an acceptable safety and tolerability profile., Registration: PROSPERO registration number CRD42024544531.

This systematic review and meta-analysis were conducted to evaluate the cardiac and kidney-related adverse effects of roxadustat for the treatment of anemia in CKD patients. 18 trials with a total of 8806 participants were identified for analysis. We employed a fixed-effects model for analysis. The pooled result revealed no significant difference in the risk of occurrence of cardiac disorders when comparing CKD patients receiving roxadustat with the placebo (RR = 1.049; CI [0.918 to 1.200]) or ESA (RR = 1.066; CI [0.919 to 1.235]), in both dialysis-dependent (DD) (RR = 1.094; CI [0.925 to 1.293]) or non-dialysis-dependent (NDD) (RR = 1.036; CI [0.916 to 1.171]) CKD patients. No significant difference was observed in the risk of kidney-related adverse events when comparing roxadustat with the placebo (RR = 1.088; CI [0.980 to 1.209]) or ESA (RR = 0.968; CI [0.831 to 1.152]), in DD (RR = 2.649; CI [0.201 to 34.981]) or NDD (RR = 1.053; CI [0.965 to 1.149]) CKD patients. A high risk of hyperkalemia was observed in the roxadustat group in DD (RR = 0.939; CI [0.898 to 0.981]). Incidence of hypertension was higher in the roxadustat for NDD patients (RR = 1.198; CI [1.042 to 1.377]), or compared to the placebo (RR = 1.374; CI [1.153 to 1.638]). In summary, the risk of cardiac or kidney-related events observed in the roxadustat was not significantly increase whether in DD or NDD patients. However, attention must be paid to the occurrence of hyperkalemia for DD patients and hypertension in NDD patients using roxadustat.

Rationale: Pharmacological mechanism of Roxadustat in the treatment of renal anemia., Patient Concerns: To investigate the efficacy and safety of combined Roxadustat and erythropoiesis stimulator (ESA) treatment of renal anemia in hemodialysis patients with secondary hyperparathyroidism., Diagnoses: A retrospective analysis was conducted on hemodialysis patients with renal anemia and secondary hyperparathyroidism treated with ESAs alone, who were admitted to our hospital from March 2022 to December 2022., Interventions: The patients were treated with Roxadustat combined with ESAs for 3 months, during which oral iron supplementation was given, and the changes in Hb levels and laboratory-related indicators before and after the combined treatment were analyzed., Outcomes: The results showed that a total of 13 patients received combination therapy, with a significant increase in Hb compared to ESAs alone (t = -3.955, P = .002). The Hb qualification rate was 38.46%, and the ∆Hb response rate was 76.92%. The parathyroid hormone significantly decreased with a statistically significant difference (Z = -2.062b, P = .039). Hemoglobin (RBC), total iron binding capacity, and serum ferritin (male) were significantly increased compared to ESAs alone. Total cholesterol and low-density lipoprotein were significantly lower than ESAs alone. The differences in the changes in the above indicators were statistically significant (P < .05). There was no statistically significant difference in changes in other laboratory-related indicators (P > .05). No adverse reactions were observed during the combined treatment of 13 patients., Lessons Subsections: The combination of Roxadustat and ESAs can effectively improve renal anemia in hemodialysis patients with secondary hyperparathyroidism, as well as improve indicators of hyperparathyroidism and blood lipid levels with high levels of safety. This combined treatment thus provides a new and safe treatment method for these patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

We aimed to compare the clinical efficacy and safety of roxadustat with erythropoiesis-stimulating agents, particularly erythropoietin (EPO), in the treatment of maintenance hemodialysis patients with renal anemia. A prospective cohort study was carried out at the Nephrology Department of the Nantong First People's Hospital and Nantong University Affiliated Hospital from December 2020 to December 2021. We compared hemoglobin (Hb) levels, serum ferritin (SF) levels, and adverse cardiovascular events between the roxadustat and EPO groups at 1, 3, and 6 months into the treatment. A total of 209 patients participated in the study, with 112 in the roxadustat group and 97 in the EPO group. At baseline, no statistically significant differences were observed between the 2 groups in terms of age, gender, weight, dialysis modality and duration, previous EPO dosage, Hb levels, SF levels, transferrin saturation, heart function classification, and blood pressure levels (P > .05). After 1 month, Hb levels in the roxadustat group were significantly higher than those in the EPO group (P < .05). However, no statistically significant differences were found between the 2 groups at 3 and 6 months (P > .05). Additionally, there were no significant differences in SF levels and the occurrence of adverse cardiovascular events between the 2 groups after treatment (P > .05). Roxadustat was superior to EPO in the initial treatment phase, while its cardiovascular safety was comparable to that of EPO., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To evaluate the long-term efficacy and safety of ripasudil-brimonidine fixed-dose combination (RBFC), a new intraocular pressure (IOP)-lowering medication for glaucoma and ocular hypertension (OHT)., Methods: This prospective, multicentre (23 sites in Japan), open-label study enrolled patients with primary open-angle glaucoma (POAG), OHT or exfoliative glaucoma and assigned them to one of four combination therapy cohorts, based on previous treatment(s) received: prostaglandin (PG) analogue (Cohort 1); PG analogue and beta-adrenoceptor blocker (β-blocker) (Cohort 2); PG analogue, β-blocker and carbonic anhydrase inhibitor (Cohort 3); or other/no treatment (Cohort 4). After a ≥ 4-week screening period, eligible patients received twice-daily RBFC for 52 weeks in addition to the treatments they were already receiving. Efficacy was assessed by change in IOP from baseline through week 52. Adverse events and adverse drug reactions (ADRs) were monitored throughout., Results: In total, 179 patients from Cohort 1 (n = 48), Cohort 2 (n = 44), Cohort 3 (n = 41) and Cohort 4 (n = 46) entered the RBFC treatment period. For all cohorts, mean IOP was significantly reduced at 11:00 (2 h after instillation of RBFC) through week 52 with the changes from baseline at week 52 of - 2.7 to - 4.1 mmHg across cohorts; all p < 0.001. Common ADRs were conjunctival hyperaemia (58%), allergic conjunctivitis (18%) and blepharitis (17%), most of which were mild in severity., Conclusion: These data demonstrated the long-term efficacy and safety of RBFC, both alone and in combination with other anti-glaucoma agents. RBFC may offer a new treatment option for the long-term management of glaucoma and OHT., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080225063., Date of Registration: 17 February 2020., (© 2024. The Author(s).)

Some aplastic anemia(AA) patients only have partial hematological responses after immunosuppressive therapy. Failure to achieve complete normalization of blood counts, particularly hemoglobin, will reduce their quality of life. This open-label pilot study was conducted to evaluate the efficacy and safety of roxadustat in this setting. A total of 14 patients with AA who had inadequate erythroid response after immunosuppressive therapy were included in the study. The primary efficacy endpoint was hemoglobin response at week 8 after roxadustat treatment. The median duration of roxadustat therapy was 14 (4-30) weeks, with 12 patients receiving roxadustat for ≥ 8 weeks. At week 8, nine patients (9/14, 64.3%) had their hemoglobin rising for at least 15 g/L, with two patients (2/14, 14.3%) achieving normal hemoglobin levels. By the last follow-up, hemoglobin responses were observed in 10 patients (10/14, 71.4%), with 4 patients(4/14, 28.6%) having normal hemoglobin levels. Roxadustat was tapered or discontinued in four responded patients; one relapsed after 12 weeks of tapering, and three maintained their response. Four patients (4/14, 28.6%) experienced mild adverse effects during therapy. Roxadustat is safe and well tolerated by patients with AA. Treatment with the hypoxia-inducible factor prolyl hydroxylase inhibitor improves hemoglobin levels in AA patients with inadequate erythroid responses., (© 2024. The Author(s).)

Objectives: To compare the efficacy and safety of hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHis), a novel agent for management of anemia in chronic kidney disease (CKD), between transplant recipients and nontransplant individuals., Methods: A retrospective analysis was conducted on nondialysis-dependent CKD stage 3 to 5 patients treated with the HIF-PHi roxadustat or daprodustat at a single institution. Patients were categorized as kidney transplant recipients (KTRs) and non-KTRs. Efficacy outcomes (hemoglobin and creatinine levels) and safety profiles (rate of adverse events [AEs], descriptions, and discontinuations due to AEs) were assessed 3 months before and 6 months after HIF-PHi initiation within and then between the groups., Results: The study comprised 82 patients (KTR: 43, non-KTR: 39). Median ages significantly differed between the KTR (52.7 years) and non-KTR (82.9 years) groups (P < .001). Roxadustat was predominantly used in the KTR group (88.4%), while daprodustat was used in the non-KTR group (94.9%, P < .001). Both groups exhibited significant increases in Hb levels at 1, 3, and 6 months post-HIF-PHi initiation (P for trend, <.001), with a relative increase in Hb level at 6 months of 16% for KTRs and 13% for non-KTRs. Creatinine levels showed no significant changes over 6 months. Although no difference was observed in drug discontinuation due to AEs, the KTR group experienced a significantly higher rate of thrombotic events (18.6 vs 2.6%, P = .049)., Conclusions: HIF-PHis demonstrate comparable efficacy for managing anemia in CKD, regardless of transplant status. However, heightened vigilance for thrombosis events is necessary during follow-up for KTRs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background/aims: Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness., Methods: Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks., Results: The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group., Conclusion: For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Introduction: Thromboembolic events have occurred in clinical trials of roxadustat. This post hoc analysis explored potential factors related to thromboembolic events in dialysis-dependent patients treated with roxadustat in four phase 3 clinical trials in Japan., Methods: Thromboembolic events with onset before and after week 12 were evaluated. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses using conditional logistic models with matched pairs of case-control data explored relationships between thromboembolic events and laboratory parameters., Results: Of the 444 patients, 56 thromboembolic events were observed in 44 patients during ≤ 52 weeks of treatment. The proportion of venous and arterial thromboembolic events gradually increased after week 12. Baseline risk factors included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), shorter dialysis vintage (< 4 months), and history of thromboembolism. The absence of concomitant intravenous or oral iron therapy (including ferric citrate) was associated with thromboembolic events before week 12 (hazard ratio 11.25; 95% confidence interval [CI] 3.36-37.71; vs presence). Case-control analysis revealed that low average transferrin saturation (< 10%; unadjusted odds ratio [OR] 6.25; 95% CI 1.52-25.62; vs ≥ 20%), high average transferrin level (≥ 2.5 g/L; unadjusted OR 4.36; 95% CI 1.23-15.39; vs < 2.0 g/L), and high average roxadustat dose (≥ 150 mg; unadjusted OR 5.95; 95% CI 1.07-33.16; vs < 50 mg) over the previous 8 weeks before the event onset were associated with thromboembolic events after week 12. However, adjustment for iron status extinguished the significant relationship between roxadustat dose and events. Multivariate case-control analysis showed that increased transferrin from baseline (≥ 1.0 g/L; adjusted OR 7.85; 95% CI 1.82-33.90; vs < 0.5 g/dL) and decreased mean corpuscular volume (< - 2 fL; adjusted OR 5.55; 95% CI 1.73-17.83; vs ≥ 0 fL) were associated with increased risk of thromboembolic events., Conclusion: In addition to established risk factors, iron deficiency may be related to thromboembolic events. Graphical Abstract available for this article., Trial Registration: NCT02780726, NCT02952092, NCT02780141, NCT02779764., (© 2024. The Author(s).)

Introduction: Risk factors for thromboembolic events in patients with dialysis-dependent chronic kidney disease (CKD) receiving roxadustat are unknown. Iron deficiency has been reported as a risk factor for thrombosis in the general population., Methods: Thromboembolic events with onset before and after week 12 in patients receiving roxadustat were evaluated in this pooled analysis of four global phase 3 trials, PYRENEES, SIERRAS, HIMALAYAS, and ROCKIES. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses with matched pairs of case-control data explored the relationship between thromboembolic events and last known laboratory parameters before event onset., Results: Of 2354 patients, 1026 thromboembolic events were observed in 568 patients. Baseline risk factors found included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), Black race, high high-sensitivity C-reactive protein, and history of thromboembolism, cardiovascular disease, or diabetes. Univariate case-control analyses revealed that high hemoglobin rate of rise (≥ 0.5 g/dL/week; odds ratio [OR] 2.09; 95% confidence interval [CI] 0.98-4.46) showed a trend towards increased risk of thromboembolic events before week 12, and high rate of hemoglobin decline was associated with events after week 12 (< - 0.5 g/dL/week; OR 3.73; 95% CI 1.68-8.27) as compared to stable hemoglobin levels (≥ - 0.1 to < 0.1 g/dL/week). Multivariate case-control analyses showed that low last known hemoglobin level (< 10 g/dL: adjusted OR 1.91; 95% CI 1.04-3.50; vs ≥ 12 g/dL) and low last known transferrin saturation (TSAT < 10%: adjusted OR 3.78; 95% CI 1.71-8.39; vs ≥ 30%) before event onset were associated with events after week 12. In patients with last known TSAT < 30%, higher roxadustat dose was associated with thromboembolic events; however, no association was observed in those with TSAT ≥ 30%., Conclusions: Among various risk factors for thromboembolic events, it is reasonable to avoid a rapid increase and decline in hemoglobin levels as well as ensure TSAT ≥ 30%, rather than increasing the roxadustat dose. Graphical Abstract available for this article., Trial Registration: NCT02278341, NCT02273726, NCT02052310, NCT02174731., (© 2024. The Author(s).)

Objective: To evaluate the efficacy and safety of roxadustat in patients with refractory non-severe aplastic anemia (NSAA) . Methods: The clinical data of patients with refractory NSAA who had been treated with roxadustat continuously for at least 3 months and followed up for more than 6 months at Peking Union Medical College Hospital from October 2020 to August 2022 were retrospectively collected. The demographic information, clinical data, treatment efficacy, adverse reactions, and outcomes were evaluated, and the factors influencing efficacy were analyzed. Results: A total of 41 patients were included. The male-to-female ratio was 16∶25, and the median age was 52 (18-84) years. The median duration of roxadustat treatment was 5 (3-20) months, and the median follow-up was 15 (6-26) months. Hematologic improvement-erythroid (HI-E) was 12.2%, 29.3%, 46.3%, 43.9%, and 30.3% at 1, 2, 3, 6, and 12 months, respectively. The rate of transfusion independence was 28.5%, 38.1%, and 33.3% at 3, 6, and 12 months, respectively. Hemoglobin returned to normal in some patients after treatment with roxadustat. The incidence of adverse events was 22%, all of which were grade Ⅰ-Ⅱ and recoverable. No factors that could affect HI-E were identified. By the end of follow-up, 45% of the patients relapsed, with a median time to relapse of 7 (3-12) months. No clonal evolution was observed, and one patient died. Conclusion: Roxadustat effectively improved anemia with good tolerance in patients with refractory NSAA.

Background: Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects., Methods: This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio., Results: 59 healthy volunteers received tenapanor 10 mg ( n  = 12 Chinese), 30 mg ( n  = 12 Chinese), or 50 mg ( n  = 12 (Chinese), n  = 11 (Caucasian)) or placebo ( n  = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean C max , AUC 0- t , and AUC 0-∞ of tenapanor-M1 increased with increasing dose level, and AUC 0- t increased approximately dose proportionally. The C max accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred., Conclusion: Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783., Competing Interests: Xin Wang, Gang Wei, and Lei Diao are full-time employees of Fosun Pharma. Han Zhao and Ai-Min Hui are ex-employees of Fosun Pharma. Yongchun Zhou is a full-time employee of Wanbang Biopharmaceuticals. The other authors declare no conflicts of interest that are relevant to the contents of this article., (Copyright © 2024 Gang Yuan et al.)

Duvelisib, a small-molecule phosphatidylinositol 3-kinase-δ,γ inhibitor, has shown efficacy for mycosis fungoides (MF) at dosage ranges of 25-100 mg twice daily (BID), but with significant toxicity. We conducted a retrospective cohort study of patients with advanced MF treated with low-dose duvelisib (15 mg every other day to BID), in an effort to minimize toxicity. A total of 7 patients were included. The overall response rate on duvelisib was 71%, with the remaining patients maintaining stable disease. Mean modified Severity Weighted Assessment Tool score improved by 57.4% and mean percent body surface area involved improved by 52%. Median progression-free survival was 10.3 months. Adverse events occurred in 4 of 7 patients, the most common being fatigue (2/7; grades 1-2), nausea (2/7; grades 1-2), and transaminitis (2/7; grade 3). Overall, low-dose duvelisib showed efficacy for advanced MF with less toxicity, providing a rationale for its use as monotherapy and potentially combinatorial therapy., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Anemia of chronic kidney disease (CKD) has a high incidence and is associated with many disease conditions. Iron dysmetabolism is an important contributor to anemia in CKD patients., Methods: ALTAI, a randomized, active-controlled, phase 4 trial, investigated the efficacy of roxadustat versus recombinant human erythropoietin (rHuEPO) on gastrointestinal iron absorption in patients with anemia of CKD (stage 4/5). The primary endpoint was change from baseline to day 15 in gastrointestinal iron absorption (serum iron area under the concentration-time curve; AUC 0-3h ) following single-dose oral iron., Results: Twenty-five patients with a mean age of 55.1 years were randomized 1:1 to roxadustat (n = 13) or rHuEPO (n = 12). Baseline iron profiles were similar between treatment groups. Change from baseline to day 15 in serum iron AUC 0-3h was not statistically significantly different between the roxadustat and rHuEPO groups. Mean (SD) change from baseline in serum iron AUC 0-3h was 11.3 (28.2) g × 3 h/dl in the roxadustat group and - 0.3 (9.7) g × 3 h/dl in the rHuEPO group. Roxadustat treatment was associated with decreased hepcidin and also increased transferrin, soluble transferrin receptor, and total iron-binding capacity (TIBC), with nominal significance. The proportion of patients experiencing one or more adverse events was 38.5% when treated with roxadustat and 16.7% with rHuEPO., Conclusions: The study showed no significant difference between roxadustat and rHuEPO in iron absorption but was underpowered because of recruitment challenges., Trial Registration: ClinicalTrials.gov Identifier NCT04655027., (© 2024. The Author(s).)

Background: Erythropoiesis-stimulating agents (ESAs) have played an important role in the treatment of renal anemia in children, but cannot improve hemoglobin to target level in some cases. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, can stimulate endogenous erythropoietin production and regulate iron metabolism even in patients with kidney failure. However, roxadustat has not yet been approved for use in children., Case-Diagnosis/treatment: We report a case of refractory renal anemia in an 80-day-old boy, who was hyporesponsive to ESAs even in combination with iron supplementation and transfusion. Compassionate use of roxadustat successfully corrected the intractable anemia. Hyperkalemia is a manageable adverse event of concern during follow-up., Conclusion: The successful experience in this case may inform the clinical utility of roxadustat for refractory renal anemia in children, which should be further confirmed by well-designed prospective clinical trials., (© 2023. The Author(s).)

Background: Postoperative nausea and vomiting (PONV) is a frequent adverse effect following laparoscopic sleeve gastrectomy. Palonosetron with a standard dosing (75 μg) schedule has been questioned due to its low efficiency in obese patients. This study aimed to investigate the effectiveness and safety of the body weight-based dosing of palonosetron in managing PONV following laparoscopic sleeve gastrectomy., Methods: A single-center, prospective, double-blinded randomized study was conducted between August 2021 and December 2021. Patients who underwent laparoscopic sleeve gastrectomy were prospectively recruited in the study. One hundred patients were randomly divided into palonosetron (Group P) and ondansetron (Group O). The demographic and clinical variables were recorded. The primary outcome of the study was the incidence of PONV between the two groups during the hospitalization. The secondary outcomes were the number of rescue anti-emetic and analgesic medications and the Functional Living Index-Emesis scores., Results: There were 50 patients in each group (Group P and Group O). There were significant differences in the scores of POVN, nausea, and vomiting favoring Group P. In Group P, the rate of patients using rescue anti-emetics was significantly lower. The incidence of complete response and proportion of patients with higher Functional Living Index-Emesis scores were significantly higher in patients using palonosetron., Conclusions: The use of palonosetron significantly reduced the incidence of PONV following laparoscopic sleeve gastrectomy. There was a significant improvement in the scores of Functional Living Index-Emesis in patients using palonosetron.

Asunaprevir, daclatasvir, and beclabuvir are direct-acting antiviral agents used in the treatment of patients infected with hepatitis C genotype 1b. This article reviews the biotransformation and disposition of these drugs in relation to the safety and efficacy of therapy. CYP3A4 and 3A5 catalyze the oxidative biotransformation of the drugs, while P-glycoprotein mediates their efflux from tissues. Asunaprevir is also a substrate for the influx transporters OATP1B1 and OATP2B1 and the efflux transporter MRP2, while beclabuvir is also a substrate for the efflux transporter BCRP. Liver disease decreases the expression of CYPs and transporters that mediate drug metabolism and disposition. Serum asunaprevir concentrations, but not those of daclatasvir or beclabuvir, are increased in patients with severe liver disease, which may produce toxicity. Pharmacogenomic variation in CYPs and transporters also has the potential to disrupt therapy with asunaprevir, daclatasvir and beclabuvir; some variants are more prevalent in certain racial groups. Pharmacokinetic drug-drug interactions, especially where asunaprevir, daclatasvir, and beclabuvir are victim drugs, are mediated by coadministered rifampicin, ketoconazole and ritonavir, and are attributable to inhibition and/or induction of CYPs and transporters. Conversely, there is also evidence that asunaprevir, daclatasvir and beclabuvir are perpetrators of drug interactions with coadministered rosuvastatin and dextromethorphan. Together, liver disease, pharmacogenomic variation and drug-drug interactions may disrupt therapy with asunaprevir, daclatasvir and beclabuvir due to the impaired function of important CYPs and transporters., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). DENALI, a phase 3b study, evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD receiving in-center or home dialysis., Methods: Eligible patients received open-label roxadustat, dosed three times weekly for 24 weeks, with an optional extension of ≤1 year. Initial dosing depended on erythropoiesis-stimulating agent (ESA) dose at screening for patients receiving ESAs (≥6 weeks) and weight-based for those not (total <6 weeks). Primary efficacy endpoints were proportion of patients with mean hemoglobin (Hb) ≥10.0 g/dL averaged over Weeks 16-24, and mean Hb change from baseline to the average during Weeks 16-24. Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were assessed., Findings: Of 281 patients screened, 203 were treated and 201 included in the full analysis set. Overall, 166 patients completed the 24-week treatment period and 126 continued into the extension period. Mean baseline Hb was 10.4 g/dL and 82.6% received in-center hemodialysis. Overall, 84.6% of patients achieved a mean Hb ≥ 10.0 g/dL averaged Weeks 16-24. Mean (standard deviation) Hb change from baseline averaged Weeks 16-24 was 0.5 (1.0) g/dL. Prespecified subgroup analyses were consistent with primary analyses. Dosing adherence was 94%. Overall, 3.0% of patients received a red blood cell transfusion at up to Week 24. TEAEs and TESAEs were reported by 71.4% and 25.6% of patients, respectively. The most frequently reported TESAEs were COVID-19 (n = 5; 2.5%), and acute myocardial infarction, pneumonia, and sepsis (each n = 4; 2.0%)., Discussion: Roxadustat effectively achieved and/or maintained mean Hb levels ≥10.0 g/dL in patients receiving dialysis. The feasibility of incorporating oral roxadustat into dialysis organizations was successfully demonstrated with high dosing adherence. No new safety signals were identified., (© 2023 The Authors. Hemodialysis International published by Wiley Periodicals LLC on behalf of International Society for Hemodialysis.)

Objective: To investigate the efficacy of roxadustat in hemodialysis patients with erythropoietin (EPO) hypo-responsive anemia., Materials and Methods: This retrospective study included 55 hemodialysis patients with erythropoietin hypo-responsive anemia at the First Affiliated Hospital of Chongqing Medical University from January to December 2020. We observed their hemoglobin (Hb) changes, inflammatory factors, and adverse reactions before and after 12 weeks of roxadustat treatment., Results: Among the 55 patients, the average age was 60.75 ± 13.96 years old, and the median dialysis age was 48 months. All patients were taken off EPO and switched to roxadustat during the follow-up period. Compared with baseline, patients' Hb was significantly increased (90.64 ± 20.01 g/L, 98.52 ± 15.89 g/L, 104.34 ± 19.15 g/L, and 107.02 ± 20.54 g/L, respectively) (p &lt; 0.05). At 12 weeks of roxadustat treatment, 34 patients (61.82%) met the target Hb levels (100 - 130 g/L). The multivariate logistic analysis showed that Hb response positively correlated with the Hb level before roxadustat treatment (p = 0.046), while responding well to roxadustat negatively correlated with blood platelet-to-lymphocyte ratio (PLR) and duration of dialysis (p = 0.029 and p = 0.046) in patients with EPO hypo-responsive anemia., Conclusion: Roxadustat could effectively improve anemia; the PLR and dialysis age were independent predictors of roxadustat efficacy in dialysis patients with EPO hypo-responsive anemia.

Background: Tenapanor, a first-in-class, minimally systemic inhibitor of intestinal sodium/hydrogen exchanger isoform 3 (NHE3), is approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults based on two randomized, placebo-controlled, phase III studies (T3MPO-1 [NCT02621892], T3MPO-2 [NCT02686138]). The open-label T3MPO-3 extension study (NCT02727751) enrolled patients who completed these studies to investigate long-term safety and tolerability of tenapanor., Methods: Patients who completed T3MPO-1 (16 weeks) or T3MPO-2 (26 weeks) were eligible for enrollment in T3MPO-3. Patients in T3MPO-3 received open-label tenapanor 50 mg twice a day for up to an additional 39 (T3MPO-1) or 26 (T3MPO-2) weeks. Treatment-emergent adverse events (TEAEs) were evaluated in the entire T3MPO-3 safety population and in patients who received a total of ≥52 weeks of tenapanor., Key Results: A total of 312 patients were enrolled in T3MPO-3; 90 received ≥52 weeks of tenapanor. TEAEs were reported in 117 (37.5%) patients in the safety population and in 52 (57.8%) patients who received ≥52 weeks of tenapanor. Diarrhea was the most common TEAE, occurring in 10.6% of the safety population and in 11.1% of patients who received ≥52 weeks of tenapanor. Most cases were mild or moderate in severity, with only two severe cases reported in the safety population. No deaths occurred during the T3MPO-3 study., Conclusions: Tenapanor was tolerable over ≥52 weeks of treatment and showed similar safety to that seen in shorter studies. Combined results of the T3MPO studies indicate that tenapanor is a valuable new treatment option for patients with IBS-C., (© 2023 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: Roxadustat is a novel oral medication used to treat anemia in CKD patients. Several studies have shown that Roxadustat can alleviate anemia in CKD patients by increasing hemoglobin levels and regulating iron metabolism. We aimed to evaluate the effect of Roxadustat on ventricular repolarization in PD patients. This study may provide a new integrated approach to the assessment and treatment of CKD., Methods: The present prospective cohort study enrolled 65 CKD patients who were treated with Roxadustat and 31 CKD patients who received conventional therapy between January 2021 and June 2022. All patients were examined for ECG in the absence of clinical symptoms and compared the ECG indicators. Demographic and clinical data of all patients were collected. All data used SPSS 18.0 for statistical analyses., Results: The T peak-to-end (Tpe) of PD patients in the Roxadustat group was remarkably slower than that of patients in the conventional group. Additionally, the Tpe/QT ratio in the conventional group was significantly elevated than that in the Roxadustat group. The results of logistic regression analysis showed that Tpe (95%CI 1.191 ~ 2.141, P = 0.002) and Roxadustat treatment (95%CI 1.357 ~ 42.121, P = 0.021) were the risk factors of PD patients with high Tp-e/QT ratio., Conclusion: In summary, we found that Roxadustat could improve ventricular repolarization in peritoneal dialysis patients, which indicated a potential cardiovascular protective effect of Roxadustat. This study might provide a new integrated approach to the assessment and treatment of CKD., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). ASPEN evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD in US dialysis organizations., Methods: This open-label, single-arm study (NCT04484857) comprised a 6-week screening period, followed by 24 weeks of treatment (with optional extension ≤1 year) and a 4-week follow-up. Patients aged ≥18 years, receiving chronic dialysis, with hemoglobin (Hb) 9.0-12.0 g/dL if converting from erythropoiesis-stimulating agents (ESAs), or <10.0 g/dL if receiving ESAs for <6 weeks, received oral roxadustat three times weekly in-center. Primary efficacy endpoints included proportion of patients with mean Hb ≥10 g/dL, averaged over weeks 16-24, and mean Hb change from baseline to the average over weeks 16-24. Safety was also assessed., Findings: Overall, 283 patients were enrolled and treated, 282 (99.6%) were included in the full analysis set, and 216 (76.3%) continued into the extension period. Most patients enrolled were from DaVita sites (71%), with the rest from US Renal Care sites (29%). Mean (standard deviation [SD]) baseline Hb was 10.6 (0.7) g/dL. Nearly all patients were prior ESA users (n = 274; 97.2%). The proportion of patients with mean Hb ≥10 g/dL during weeks 16-24 was 83.7% (95% confidence interval 78.9-88.6). Mean (SD) Hb increase from baseline to the average over weeks 16-24 was 0.2 (1.0) g/dL. During the treatment period, 82 (29.0%) patients reported treatment-emergent serious adverse events (TESAEs). The most common TESAEs were COVID-19 pneumonia (n = 10; 3.5%), acute respiratory failure (n = 9; 3.2%), COVID-19 (n = 7; 2.5%), acute myocardial infarction (n = 7; 2.5%), and fluid overload (n = 6, 2.1%)., Discussion: Roxadustat was effective in maintaining Hb in patients with anemia of CKD on dialysis in large, community-based dialysis organizations., (© 2023 The Authors. Hemodialysis International published by Wiley Periodicals LLC on behalf of International Society for Hemodialysis.)

Hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI) is a novel agent for the treatment of renal anemia. HIF-PHI increases endogenous erythropoietin production by inhibiting the degradation of an erythropoietin transcription factor. Although beneficial effects are expected from HIF-PHI, its novel mechanism raises concerns regarding the risk of potential adverse events. The cases of hypothyroidism, which had not been reported in clinical trials, were reported after the administration of roxadustat in a real-world setting. However, the effects of HIF-PHIs on thyroid function have not yet been fully evaluated. This study aimed to assess the clinical impact of HIF-PHIs on thyroid function using the Japanese Adverse Drug Event Report database, a spontaneous reporting system in Japan, because HIF-PHIs were made available in Japan before they were available in other countries. Although a disproportionality signal for hypothyroidism was detected with roxadustat (reporting odds ratio [ROR]:22.1, 95% confidence interval [CI]:18.3-26.7, no signals were detected with another HIF-PHI, daprodustat (ROR:1.3, 95%CI:0.3-5.4), and epoetin beta pegol (ROR:1.2, 95%CI:0.5-2.7). Signals of hypothyroidism due to roxadustat were also detected regardless of age or sex. Approximately 50% of hypothyroidism cases were reported within 50 days of starting roxadustat use. These results indicate that roxadustat use may be related to the development of hypothyroidism. The need for monitoring of thyroid function should be alerted during roxadustat administration regardless of age or sex., (© 2023, The American College of Clinical Pharmacology.)

Anemia is a common side effect of myelosuppressive chemotherapy; however, chemotherapy-induced anemia (CIA) management options are suboptimal. We evaluated the efficacy and safety of roxadustat in this setting. This open-label Phase 2 study included patients with non-myeloid malignancies and CIA (hemoglobin [Hb] ≤10 g/dL) who had planned concurrent myelosuppressive chemotherapy for ≥8 additional weeks. Oral roxadustat was administered for ≤16 weeks (starting dose 2.0 or 2.5 mg/kg, then titrated every 4 weeks). The primary efficacy endpoint was mean maximum change in Hb within 16 weeks of baseline without red blood cell (RBC) transfusion. Patients were assigned to roxadustat 2.0 (n = 31) or 2.5 mg/kg (n = 61) starting doses, and 89 were assessed for efficacy. The mean (standard deviation) maximum Hb change from baseline without RBC transfusion was 2.4 (1.5) and 2.5 (1.5) g/dL in the roxadustat 2.0 and 2.5 mg/kg groups, respectively. Median (range) time to Hb increase of ≥2 g/dL was 71 (57-92) days. Twelve patients (14.5%) had RBC transfusions (Week 5 to the end of treatment). Roxadustat was efficacious regardless of tumor type and chemotherapy regimen. Deep vein thrombosis (DVT) and pulmonary embolism (PE) occurred in 14 (15.2%) and nine (9.8%) patients, respectively, and three had serious adverse events attributed to roxadustat in the opinion of the investigators (PE: n = 2 [2.2%]; DVT: n = 1 [1.1%]). Roxadustat increased Hb in patients with CIA regardless of tumor type and chemotherapy regimen. Adverse events were consistent with observations in patients with advanced-stage malignancies., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Anemia is a common complication of chronic kidney disease (CKD), and its prevalence rises as the disease progresses. Intravenous or subcutaneous erythropoiesis-stimulating agents (ESAs) are advised to treat CKD-associated anemia, since shortage of erythropoietin (EPO) and iron are the main cause of anemia. However, ESA resistance and safety have spurred a lot of interest in the development of alternate anemia therapies. Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that increases erythropoiesis and may modulate iron metabolism, was recently licensed in China, Chile, South Korea, Japan and the European Union for the treatment of CKD-related anemia. Despite this, clinical trials have shown a number of adverse effects, including cardiovascular disease, hyperkalemia, and infections. In addition, of concern is roxadustat's possible effects on other organs and systems. In this review, based on clinical evidence, we discuss the potentially detrimental effects of roxadustat to the known biology on systems other than kidney, and the need for long-term follow-up in order for roxadustat to be approved in more countries in the future.

Introduction: This study was conducted to elucidate the safety of roxadustat, an oral medication, in patients with non-dialysis-dependent (NDD) or incident dialysis dialysis-dependent (ID-DD) chronic kidney disease (CKD)., Methods: Safety results from four phase 3, randomized, open-label studies comparing roxadustat to an erythropoiesis-stimulating agent (ESA) in men and women with NDD or ID-DD CKD with anemia were pooled and evaluated. Endpoints were time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), all-cause mortality, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8- and 1.3-margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized., Results: In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA). Roxadustat was comparable to ESA for risk of MACE (HR 0.79, 95% CI 0.61-1.02), MACE+ (HR 0.78, 95% CI 0.62-0.98), and all-cause mortality (HR 0.78, 95% CI 0.57-1.05). TEAEs were comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 (IR/100) patient-exposure years 56.1 vs. 53.5], TEAEs leading to study drug discontinuation (IR/100 patient-exposure years 6.7 vs. 5.1), and TEAEs leading to death (IR/100 patient-exposure years 6.9 vs. 7.4)., Conclusion: There was no evidence of increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAEs occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued the study drug because of an adverse event., Clinical Trial Registration Numbers: DOLOMITES, 1517-CL-0610 [NCT02021318]; HIMALAYAS, FGCL-4592-063 [NCT02052310]; SIERRAS, FGCL-4592-064 [NCT02273726]; and ROCKIES, D5740C00002 [NCT02174731]., (© 2023. The Author(s).)

Introduction: Angiotensin-converting enzyme (ACE) inhibitors are a mainstay of antihypertensive therapy. Quinapril hydrochloride, a less commonly used, and less-studied ACE inhibitor has been approved for its primary use in hypertension. Studies also indicate its off-label use for congestive heart failure and diabetic nephropathy. The ANDI and TREND trials have been pivotal in demonstrating the effectiveness of quinapril., Areas Covered: The authors conducted a review of the literature analyzing the clinical efficacy and safety profile of quinapril. This review discusses the development of quinapril, provides an updated summary of the indications and contraindications, and presents a comparison with other ACE inhibitors., Expert Opinion: Quinapril is a safe and well-tolerated antihypertensive medication with a favorable safety profile compared to other ACE inhibitors. However, a lack of ample recent clinical trials and post-marketing data investigating the efficacy of quinapril in large cohorts has resulted in limited use in clinical practice. Quinapril may be an effective antihypertensive option for elderly populations as well as those who cannot tolerate the side effects profiles of other ACE inhibitors and as an additional treatment option for patients with heart failure with preserved ejection fraction.

The incidence of chronic kidney disease (CKD) is increasing worldwide and the current prevalence rate is 13.4%. There are > 120 million CKD patients in China and this number is expected to increase. One of the main abnormalities in patients with CKD and kidney impairment is decreased synthesis of erythropoietin (EPO), which causes anemia and affects iron metabolism. The probability of developing is higher in anemia patients with CKD than in the general population, and the incidence increases as kidney function decreases. Deficient EPO production by the kidney is the most important cause of renal anemia. Notably, anemia in patients with CKD has multiple causes, such as bleeding caused by platelet dysfunction, iron deficiency due to digestive and absorption disorders of the gastrointestinal tract, and shorter red blood cell life. Anemia is also a leading cause of hospitalization in patients with CKD. A new oral medication to treat renal anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor called roxadustat (FG-4592), regulates iron metabolism and promotes erythropoiesis. This drug has a therapeutic effect on patients with CKD. Roxadustat showed advantages over EPO in clinical experiments. This review summarizes the mechanisms of action, clinical applications, effectiveness, and safety of roxadustat.

Introduction: Dexamethasone (DEX)-sparing strategy with 5-hydroxytryptamine-3 receptor antagonist (5HT3RA) and aprepitant (APR), as triplet antiemetic prophylaxis, is associated with poor control of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving carboplatin (CBDCA)-based chemotherapy. This study aimed to evaluate whether using palonosetron (PALO) as a 5HT3RA provides superior control with CINV than first-generation (1st) 5HT3RA in triplet antiemetic prophylaxis with a DEX-sparing strategy., Methods: Pooled patient-level data from a nationwide, multicenter, and prospective observational study were analyzed to compare the incidence of CINV between patients administered PALO and 1st 5HT3RA in combination with 1-day DEX and APR., Results: No significant differences were observed in the incidence of CINV, pattern of CINV, or severity of nausea by type of 5HT3RA in triplet antiemetic prophylaxis with DEX-sparing strategy. In both groups, the incidence of nausea gradually increased from day 3, peaked on day 4 or 5, and then declined slowly. The visual analog scale scores in the delayed phase remained high throughout the 7-day observation period., Conclusion: Careful patient selection and symptom monitoring are needed when implementing the DEX-sparing strategy in triplet antiemetic prophylaxis for patients undergoing CBDCA-based chemotherapy. Furthermore, additional strategies may be needed to achieve better control of delayed CINV., (© 2023 S. Karger AG, Basel.)

Introduction: Pixantrone is a novel aza-anthracenedione with antineoplastic activity, currently approved for multiply relapsed/refractory diffuse large B-cell lymphoma (DLBCL), even if real-life data are limited., Methods: We investigated pixantrone efficacy and safety in clinical practice, as 3 rd or 4 th line therapy. We retrospectively analyzed a cohort of 37 R/R DLBCL patients managed in 8 Tuscan onco-hematological centers. Pixantrone, 50 mg/m 2 , was administered on days 1, 8, 15 of a 28 days cycle for up to 6 cycles. Response to therapy was evaluated according to the Lugano 2014 classification., Results: Pixantrone was administered as 3 rd or 4 th line in 24/37 (64.9%) and 13/37 (35.1%) cases. Overall response rate and CR rate were 43.2% and 32.4%. After a median follow-up of 6 months, 17/37 patients (46%) were alive, the main cause of death was progressive disease (14/37 cases, 37.9%). Median PFS was 3 months, median DOR was 17.9 months, and median OS was 9.7 months. A significant proportion of patients achieved a long-lasting response >12 months (8/37 cases). IPI>2 showed a trend toward inferior PFS., Conclusion: In this real-life setting, pixantrone demonstrated appreciable efficacy in a population with poor prognosis; in a small proportion of cases, it can be associated with long-term remission., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Roxadustat (ROX) is a new medication for anemia as a complication of chronic kidney disease (CKD). Our meta-analysis aims to evaluate the efficacy and safety of ROX, especially on the cardiovascular risks, for anemia in NDD-CKD patients., Methods: Electronic databases were searched systematically from inception to July 2021 to look for randomized control trials (RCTs) that evaluated ROX NDD-CKD patients. Hemoglobin level and iron utilization parameters, including ferritin, serum iron, transferrin saturation (TSAT), total iron-binding capacity (TIBC), transferrin, and hepcidin were analyzed for efficacy. Pooled risk ratios (RRs) and standardized mean differences (SMDs) were calculated and presented with their 95% confidential intervals (CIs)., Results: Nine RCTs included a total of 3,175 patients in the ROX group and 2,446 patients in the control group. When compared the control group, ROX increased Hb level significantly (SMD: 1.65; 95% CI: 1.08, 2.22; P< 0.00001) and improved iron utilization parameters by decreasing ferritin (SMD: -0.32; 95% CI: -0.51, -0.14; P = 0.0006), TSAT (SMD: -0.19; 95% CI: -0.32, -0.07; P = 0.003), and hepcidin (SMD: -0.74; 95% CI: -1.09, -0.39; P< 0.0001) and increasing TIBC (SMD: 0.99; 95% CI: 0.76, 1.22; P< 0.00001) and transferrin (SMD: 1.20; 95% CI: 0.70, 1.71; P< 0.00001). As for safety, ROX was associated with higher serious adverse effects (RR: 1.07; 95% CI: 1.01, 1.13; P = 0.01), deep venous thrombosis (DVT) (RR: 3.80; 95% CI: 1.5, 9.64; P = 0.08), and hypertension (HTN) (RR: 1.37; 95% CI: 1.13, 1.65; P = 0.001)., Conclusion: We concluded that ROX increased Hb level and improved iron utilization parameters in NDD-CKD patients, but ROX was associated with higher serious adverse effects, especially DVT and HTN. Our results support the use of ROX for NDD-CKD patients with anemia. However, higher-quality RCTs are still needed to ensure its safety and risk of thrombosis., Competing Interests: The authors have declared that no competing interests exist.

Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naive and central memory CD4 T cells and naive CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs, and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Anemia is the predominant cytopenia in myelodysplastic syndromes (MDS) and treatment options are limited. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia of chronic kidney disease in the UK, EU, China, Japan, South Korea, and Chile. MATTERHORN is a phase 3, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of roxadustat in anemia of lower risk-MDS. Eligible patients had baseline serum erythropoietin ≤ 400 mIU/mL, and a low packed RBC transfusion burden. In this open-label (OL), dose-selection, lead-in phase, enrolled patients were assigned to 1 of 3 roxadustat starting doses (n = 8 each): 1.5, 2.0, and 2.5 mg/kg. The primary efficacy endpoint of the OL phase was the proportion of patients with transfusion independence (TI) for ≥ 8 consecutive weeks in the first 28 treatment weeks. A secondary efficacy endpoint was the proportion of patients with a ≥ 50% reduction in RBC transfusions over an 8-week period compared with baseline. Adverse events were monitored. Patients were followed for 52 weeks. Of the 24 treated patients, TI was achieved in 9 patients (37.5%) at 28 and 52 weeks; 7 of these patients were receiving 2.5 mg/kg dose when TI was achieved. A ≥ 50% reduction in RBC transfusions was achieved in 54.2% and 58.3% of patients at 28 and 52 weeks, respectively. Oral roxadustat dosed thrice weekly was well tolerated. There were no fatalities or progression to acute myeloid leukemia. Based on these outcomes, 2.5 mg/kg was the chosen starting roxadustat dose for the ongoing double-blind study phase., (© 2021 Wiley Periodicals LLC.)

Protein arginine methyltransferase 3 (PRMT3) is a co-activator of liver X receptor capable of selectively modulating hepatic triglyceride synthesis. Here we investigated whether pharmacological PRMT3 inhibition can diminish the hepatic steatosis extent and lower plasma lipid levels and atherosclerosis susceptibility. Hereto, male hyperlipidemic low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet and injected 3 times per week intraperitoneally with PRMT3 inhibitor SGC707 or solvent control. Three weeks into the study, SGC707-treated mice developed severe pruritus and scratching-associated skin lesions, leading to early study termination. SGC707-treated mice exhibited 50% lower liver triglyceride stores as well as 32% lower plasma triglyceride levels. Atherosclerotic lesions were virtually absent in all experimental mice. Plasma metabolite analysis revealed that levels of taurine-conjugated bile acids were ~ threefold increased (P < 0.001) in response to SGC707 treatment, which was paralleled by systemically higher bile acid receptor TGR5 signalling. In conclusion, we have shown that SGC707 treatment reduces hepatic steatosis and plasma triglyceride levels and induces pruritus in Western-type diet-fed LDL receptor knockout mice. These findings suggest that pharmacological PRMT3 inhibition can serve as therapeutic approach to treat non-alcoholic fatty liver disease and dyslipidemia/atherosclerosis, when unwanted effects on cholesterol and bile acid metabolism can be effectively tackled., (© 2022. The Author(s).)

Purpose: We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone., Patients and Methods: Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate)., Results: Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% ( P < .001) and 0.3% versus 3.6% ( P < .001), respectively., Conclusion: FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting., Competing Interests: Akito HataConsulting or Advisory Role: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, MSDSpeakers' Bureau: Boehringer Ingelheim, Lilly, Chugai Pharma, AstraZeneca, Taiho PharmaceuticalResearch Funding: Boehringer Ingelheim (Inst), MSD (Inst), Lilly (Inst), AstraZeneca (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai and Roche (Inst) Naoki InuiSpeakers' Bureau: Chugai Pharma, AstraZeneca and Daiichi Sankyo, Lilly, Nippon Boehringer Ingelheim, Novartis, Ono Yakuhin, Taiho PharmaceuticalResearch Funding: Chugai Pharma, Daiichi Sankyo and UCB Japan, Lilly, Nippon Boehringer Ingelheim, MSD K K, Taiho Pharmaceutical Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co, Ltd (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Masahiro MoriseSpeakers' Bureau: Chugai and Roche, AstraZeneca, Ono Pharmaceutical, LillyResearch Funding: Boehringer Ingelheim (Inst), Novartis (Inst), AstraZeneca (Inst), Lilly (Inst), Taiho Pharmaceutical (Inst), Chugai and Roche (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), Merck Serono (Inst), Kissei Pharmaceutical (Inst) Masayuki TakedaHonoraria: AstraZeneca Japan, Chugai Pharma, Bristol Myers Squibb Company, Novartis, Ono Pharmaceutical, Boehringer Ingelheim Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K K, Yakult Honsha, Kyowa Kirin Naofumi ShinagawaResearch Funding: Olympus Kaoru KubotaHonoraria: Bristol Myers Squibb Japan, Daiichi Sankyo, Boehringer Ingelheim, Taiho Pharmaceutical, Lilly Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Nihonkayaku, Takeda, PfizerResearch Funding: Daiichi Sankyo (Inst), Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Ono Pharmaceutical (Inst) Toshiaki SaekiResearch Funding: Taiho Pharmaceutical (Inst), Eisai (Inst) Tomohide TamuraHonoraria: Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, MSD, CMIC, Lilly, NihonkayakuNo other potential conflicts of interest were reported.

Objective: Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous T-cell malignancies representing 5%-10% of aggressive lymphomas. The prognosis is poor for patients with relapsed/refractory (R/R) disease, with a median overall survival of less than 6 months and no standardized treatments. We discuss the role of the phosphatidylinositol 3-kinase (PI3K) γδ inhibitor duvelisib as bridge to allotransplantation in a patient with R/R PTCL., Methods: Case report., Results: A 55-year-old woman diagnosed with relapsed nodal PTCL with T-follicular helper phenotype received PI3K γδ inhibitor duvelisib in the context of the phase II PRIMO clinical trial. After two cycles at a dose of 75 mg twice daily, the patient achieved complete response (CR), which was subsequently consolidated with human leukocyte antigen fully matched unrelated donor allotransplantation. No major toxicities were recorded during the duvelisib treatment period or during hospitalization for allotransplantation. At the latest follow-up, the patient was alive and still in CR 10 months posttransplant., Conclusions: Duvelisib should be further explored as a bridge to allotransplantation in patients with R/R PTCL, given the success and low toxicity in our patient.

Phosphodiesterase (PDE) 4 inhibitors prevent the metabolism of cyclic adenosine monophosphate, thereby reducing inflammation. Inhaled PDE4 inhibitors aim to restrict systemic drug exposure to enhance the potential for clinical benefits (in the lungs) versus adverse events (systemically). The orally administered PDE4 inhibitor roflumilast reduces exacerbation rates in the subgroup of chronic obstructive pulmonary disease patients with a history of exacerbations and the presence of chronic bronchitis, but can cause PDE4 related adverse effects due to systemic exposure. CHF6001 is an inhaled PDE4 inhibitor, while inhaled ensifentrine is an inhibitor of both PDE3 and PDE4; antagonism of PDE3 facilitates smooth muscle relaxation and hence bronchodilation. These inhaled PDE inhibitors have both reported positive findings from early phase clinical trials, and have been well tolerated. Longer term trials are needed to firmly establish the clinical benefits of these drugs., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: This integrated phase 3 analysis examined efficacy and cardiovascular safety for roxadustat vs erythropoiesis-stimulating agents (ESAs) in dialysis-dependent patients., Methods: Efficacy and safety results from four phase 3, randomized, open-label studies comparing roxadustat to ESAs (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES) in dialysis-dependent patients with anemia of chronic kidney disease (CKD) were evaluated by study, pooled population and in two subgroups: incident dialysis and stable dialysis. The primary efficacy endpoint per study was hemoglobin change from baseline (CFB) to weeks 28-36 using least-squares mean difference (LSMD) without rescue therapy. Pooled safety endpoints included time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality [ACM]) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8 and 1.3 margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized., Results: In total, 4714 patients were randomized (2354 roxadustat; 2360 ESA). Hemoglobin CFB to weeks 28-36 achieved non-inferiority for roxadustat vs ESA in each study. Roxadustat was non-inferior to ESA for risks for MACE and MACE+ in the entire cohort (MACE: HR 1.09, 95% CI 0.95-1.26; MACE+ : HR 0.98, 95% CI 0.86-1.11) and similar to the incident dialysis and stable dialysis subgroups; ACM results were consistent with MACE and MACE+ (HR 1.13, 95% CI 0.95-1.34). TEAEs were generally comparable between groups., Conclusion: Roxadustat improved hemoglobin similarly to ESA while demonstrating comparable cardiovascular and overall safety profiles in a wide spectrum of dialysis-dependent patients with anemia of CKD. Roxadustat represents an oral alternative to ESAs for achieving a target hemoglobin for anemia of CKD in dialysis-dependent patients., (© 2021. The Author(s).)

Background: Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia., Methods: In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphate 6.0-10.0 mg/dl) and a 1.5 mg/dl increase after phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks of treatment with tenapanor were rerandomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period), and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy end point was the difference in the change in serum phosphate from the end of the randomized treatment period to the end of the randomized withdrawal period, among participants who achieved ≥1.2 mg/dl decrease in serum phosphate during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set., Results: Of 564 eligible participants randomized to receive tenapanor ( n =423) or sevelamer carbonate ( n =141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were rerandomized to tenapanor ( n =128) or placebo ( n =127) during the randomized withdrawal period. In the efficacy analysis set ( n =131), the difference in estimated mean change in serum phosphate level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was -1.4 mg/dl ( P <0.0001); in the ITT analysis set ( n =243), the estimated mean difference was -0.7 mg/dl ( P =0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16%-23% across the three study periods) compared with tenapanor (11%-17%)., Conclusions: Tenapanor reduced serum phosphate concentrations and maintained control of serum phosphate in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile., Competing Interests: A.J. Bleyer reports no affiliation with Ardelyx, Inc. aside from his role as Principal Investigator in the PHREEDOM study. A.L. Silva reports receiving research funding from Ardelyx, Inc. D.E. Weiner reports being the Medical Director of Clinical Research for Dialysis Clinic, Inc., with support paid to his institution by Dialysis Clinic, Inc.; he reports consulting for Akebia, Cara Therapeutics, Janssen Biopharmaceuticals, and Tricida, and has no affiliation with or received funding from Ardelyx, Inc., aside from his role as site Principal Investigator in several tenapanor trials. D.P. Rosenbaum reports being an employee of, and having an ownership interest in, Ardelyx, Inc. G.A. Block reports being a Director for Ardelyx, Inc. and is the Associate Chief Medical Officer for US Renal Care, Inc. G.M. Chertow reports being a consultant to, and has equity ownership interest in, Ardelyx, Inc. R.I. Lynn has no affiliation with Ardelyx, Inc. aside from his role as Principal Investigator in the PHREEDOM and NORMALIZE studies. Y. Yang reports being an employee of Ardelyx, Inc., (Copyright © 2021 by the American Society of Nephrology.)

Background: CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525)., Methods: Fifty-one patients received oral treatment with CGM097 10-400 mg 3qw (n = 31) or 300-700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models describing the effect of CGM097 on circulating platelet and PD kinetics., Results: No dose-limiting toxicities were reported in any regimens. The most common treatment-related grade 3/4 AEs were haematologic events. PK/PD models well described the time course of platelet and serum GDF-15 changes, providing a tool to predict response to CGM097 for dose-limiting thrombocytopenia and GDF-15 biomarker. The disease control rate was 39%, including one partial response and 19 patients in stable disease. Twenty patients had a cumulative treatment duration of >16 weeks, with eight patients on treatment for >32 weeks. The MTD was not determined., Conclusions: Despite delayed-onset thrombocytopenia frequently observed, the tolerability of CGM097 appears manageable. This study provided insights on dosing optimisation for next-generation HDM2 inhibitors., Translational Relevance: Haematologic toxicity with delayed thrombocytopenia is a well-known on-target effect of HDM2 inhibitors. Here we have developed a PK/PD guided approach to optimise the dose and schedule of CGM097, a novel HDM2 inhibitor, using exposure, platelets and GDF-15, a known p53 downstream target to predict patients at higher risk to develop thrombocytopenia. While CGM097 had shown limited activity, with disease control rate of 39% and only one patient in partial response, the preliminary data from the first-in-human escalation study together with the PK/PD modeling provide important insights on how to optimize dosing of next generation HDM2 inhibitors to mitigate hematologic toxicity., (© 2021. The Author(s).)

Background and Objectives: We evaluated the efficacy and cardiovascular safety of roxadustat versus placebo by analyzing data pooled from three phase 3 studies of roxadustat in patients with non-dialysis-dependent CKD and CKD-related anemia., Design, Setting, Participants, & Measurements: In the three phase 3, double-blind studies of roxadustat versus placebo evaluating the treatment of CKD-related anemia in patients not requiring dialysis, the primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy. The primary cardiovascular safety end point was a composite measure of major adverse cardiovascular events (MACE; all-cause mortality, myocardial infarction, stroke). MACE plus (MACE+; MACE plus unstable angina and heart failure requiring hospitalization) and all-cause mortality were key secondary safety end points. These safety end points were adjudicated., Results: A total of 4277 patients with non-dialysis-dependent CKD were randomized (roxadustat, n =2391; placebo, n =1886). Baseline characteristics were comparable between groups; the mean (SD) hemoglobin was 9.1 (0.7) g/dl and mean eGFR was 20 (12) ml/min per 1.73 m 2 . Patients treated with roxadustat versus those treated with placebo showed a mean change from baseline in hemoglobin averaged over weeks 28-52, regardless of rescue therapy, of 1.9 versus 0.2 g/dl, a treatment difference of 1.7 (95% confidence interval [95% CI], 1.7 to 1.8). Roxadustat reduced the need for red blood cell transfusion in the first 52 weeks versus placebo (6.1 versus 20.4 per 100 patient-exposure years, respectively; hazard ratio [HR], 0.26; 95% CI, 0.21 to 0.32). There were no increased risks of MACE (HR, 1.10; 95% CI, 0.96 to 1.27), MACE+ (HR, 1.07; 95% CI, 0.94 to 1.21), all-cause mortality (HR, 1.08; 95% CI, 0.93 to 1.26), or individual MACE+ components in patients treated with roxadustat versus those treated with placebo., Conclusions: Roxadustat was more effective than placebo at increasing hemoglobin in patients with non-dialysis-dependent CKD and anemia, while decreasing transfusion rate and being noninferior to placebo with respect to risk of MACE., Clinical Trial Registry Name and Registration Number: A Study of FG-4592 for the Treatment of Anemia in Chronic Kidney Disease Patients Not Receiving Dialysis, NCT01750190; Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not Requiring Dialysis (ALPS), NCT01887600; Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis, NCT02174627., (Copyright © 2021 by the American Society of Nephrology.)

Introduction: Retinopathy of prematurity (ROP) is a vascular proliferative disorder that occurs in preterm infants. Existing treatments are only indicated in severe ROP cases due to the high invasiveness and the potential risk of irreversible side effects. We previously elucidated that ripasudil, a selective inhibitor of the Rho-associated protein kinase, has the ability to inhibit abnormal retinal neovascularisation in animal models. In addition, ripasudil eye drops (Glanatec ophthalmic solution 0.4%) have been already used for the treatment of glaucoma. Since eye drop therapy is less invasive, early intervention for ROP is possible. The purpose of this phase I/II trial is to evaluate the safety and efficacy of ripasudil eye drops for preterm infants with ROP., Methods and Analysis: This is a multicentre, open-label, single-arm phase I/II trial. To evaluate the safety and efficacy of ripasudil as much as possible, ripasudil will be administered to all enrolled preterm infants with zone I/II, stage 1, or worse ROP. The safety and efficacy of ripasudil in treated patients will be assessed in comparison to a historical control group. Because this is the first trial of ripasudil in preterm infants, a dose-escalation study (once daily for 1 week, then two times per day for 2 weeks) will be conducted in phase I. After obtaining approval from the independent data and safety monitoring board to continue the trial after the completion of phase I, phase II will be conducted. In phase II, ripasudil eye drops will be administered two times per day for 12 weeks. The primary endpoint in phase II is also safety. Efficacy and pharmacokinetics will be evaluated as secondary endpoints., Ethics and Dissemination: This study protocol was approved by the institutional review board at each of the participating centres. Data will be presented at international conferences and published in peer-reviewed journals., Trial Registration Numbers: NCT04621136 and jRCT2071200047., Competing Interests: Competing interests: SN and Kowa Co., Ltd. (Japan) have disclosed the patent WO 2014/174747., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Netupitant/palonosetron (NEPA; Akynzeo ® ), available in oral and intravenous (IV) formulations, is a fixed-dose combination of the neurokinin 1 (NK1) receptor antagonist netupitant (or the prodrug, fosnetupitant, in the IV formulation) and the second-generation serotonin 3 (5-HT 3 ) receptor antagonist palonosetron. Administered as a single dose, (fos)netupitant/palonosetron (in combination with dexamethasone) is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in adults. In clinical trials, (fos)netupitant/palonosetron plus dexamethasone was associated with high complete response rates (no emesis and no rescue medication) in the acute, delayed and overall phases in patients receiving highly or moderately emetogenic chemotherapy, with efficacy maintained over multiple cycles. Further, oral netupitant/palonosetron was found to be superior to palonosetron and non-inferior to aprepitant plus granisetron in preventing CINV in individual trials. Both the oral and IV formulations of the drug combination are well tolerated. The fixed-dose combination is concordant with guideline recommendations and provides a simple and convenient option for prophylaxis against acute and delayed CINV in patients receiving highly or moderately emetogenic chemotherapy., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Liver malignant tumors (LMTs) represent a serious adverse drug event associated with drug-induced liver injury. Increases in endocrine-disrupting chemicals (EDCs) have attracted attention in recent years, due to their liver function-inhibiting abilities. Exposure to EDCs can induce nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, which are major etiologies of LMTs, through interaction with nuclear receptors (NR) and stress response pathways (SRs). Therefore, exposure to potential EDC drugs could be associated with drug-induced LMTs. However, the drug classes associated with LMTs and the molecular initiating events (MIEs) that are specific to these drugs are not well understood. In this study, using the Food and Drug Administration Adverse Event Reporting System, we detected LMT-inducing drug signals based on adjusted odds ratios. Furthermore, based on the hypothesis that drug-induced LMTs are triggered by NR and SR modulation of potential EDCs, we used the quantitative structure-activity relationship platform for toxicity prediction to identify potential MIEs that are specific to LMT-inducing drug classes. Events related to cell proliferation and apoptosis, DNA damage, and lipid accumulation were identified as potential MIEs, and their relevance to LMTs was supported by the literature. The findings of this study may contribute to drug development and research, as well as regulatory decision making.