Efficacy and Adverse Effects of Atrasentan in Patients with Diabetic Nephropathy: A Meta-Analysis.

Background: About 30% of Type 1 diabetes (T1DM) patients and 40% of Type 2 diabetes (T2DM) patients were diagnosed with diabetic nephropathy, which has also greatly affected the global end-stage renal disease (ESRD) outcome. Atrasentan is a selective endothelin receptor type A (ETA) antagonist initially studied for the potential treatment of cancer. However, the role of Atrasentan was not sure in the DM. Methods: The machine searches eight databases to find studies examining the impact of Atrasentan in people with diabetic nephropathy both domestically and overseas. Type of Study Design RCTs have been published on Atrasentan's effects in patients with chronic kidney disease.Utilizing RevMan 5.3 software, data analysis was carried out following a thorough assessment of the quality of the literature. Results: This meta-analysis has included 4 papers for statistics. They were all regarded as being random controlled trials. According to 4 studies, the test group's urinary albumin/creatinine ratio (UACR) was significantly lower than the control group's (standardized mean difference (SMD): -222.47; 95% confidence interval (CI): -367.57, -77.38; P < .01), as were the test group's prevalence of cardiovascular disease (OR: 0.83; 95% CI: 0.73, 0.95; P < .01) and adverse reactions (OR: 1.00; 95% CI: 1.00). Conclusion: Atrasentan improves the UACR in individuals with chronic kidney disease as compared to the control category. However, these findings need to be confirmed by more high-quality research. Further studies could focus on the effect of the Atrasentan on the diabetic nephropathy management,which will shed light on the treatment of diabetic nephropathy.

DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS.

BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

Preventive Effect of Clazosentan against Cerebral Vasospasm after Clipping Surgery for Aneurysmal Subarachnoid Hemorrhage in Japanese and Korean Patients.

BACKGROUND: Clazosentan has been explored worldwide for the prophylaxis of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). In a dose-finding trial (CONSCIOUS-1) conducted in Israel, Europe, and North America, clazosentan (1, 5, and 15 mg/h) significantly reduced the incidence of cerebral vasospasm, but its efficacy in Japanese and Korean patients was unknown. We conducted a double-blind comparative study to evaluate the occurrence of cerebral vasospasm in Japanese and Korean patients with aSAH. METHODS: The aim of this multicenter, double-blind, randomized, placebo-controlled, dose-finding phase 2 clinical trial, was to evaluate the efficacy, pharmacokinetics, and safety of clazosentan (5 and 10 mg/h) against cerebral vasospasm after clipping surgery in Japanese and Korean patients with aSAH. Patients aged between 20 and 75 years were administered the study drug within 56 h after the aneurysm rupture and up to day 14 post-aSAH. The incidence of vasospasm, defined as an inner artery diameter reduction of major intracranial arteries ≥34% based on catheter angiography, was compared between each treatment group. Cerebral infarction due to vasospasm at 6 weeks and patients' outcome at 3 months was also compared. RESULTS: Among 181 enrolled patients, 158 completed the study and were analyzed. The incidence of vasospasm up to day 14 after aSAH onset was 80.0% in the placebo group (95% CI 67.0-89.6), 38.5% in the 5 mg/h clazosentan group (95% CI 25.3-53.0), and 35.3% in the 10 mg/h clazosentan group (95% CI 22.4-49.9), indicating that the incidence of vasospasm was significantly reduced by clazosentan treatment (placebo vs. 5 mg/h clazosentan, p < 0.0001; placebo vs. 10 mg/h clazosentan, p < 0.0001). The occurrence of cerebral infarction due to vasospasm was 20.8% in the placebo group (95% CI 10.8-34.1), 3.8% in the 5 mg/h clazosentan group (95% CI 0.5-13.2), and 4.2% in the 10 mg/h clazosentan group (95% CI 0.5-14.3), indicating that clazosentan significantly reduced the occurrence of cerebral infarctions caused by vasospasm (placebo vs. 5 mg/h clazosentan, p = 0.0151; placebo vs. 10 mg/h clazosentan, p = 0.0165). The overall incidence of all-cause death and/or vasospasm-related morbidity/mortality was significantly reduced in the 10 mg/h clazosentan group compared with the placebo group (p = 0.0003). CONCLUSION: These results suggest that clazosentan prevents cerebral vasospasm and subsequent cerebral infarction, and could thereby improve outcomes after performing a clipping surgery for aSAH in Japanese and Korean patients.

A Meta-Analysis and Indirect Comparison of Endothelin A Receptor Antagonist for Castration-Resistant Prostate Cancer.

BACKGROUND: Endothelin A (ET-A) receptor antagonists including zibotentan and atrasentan, have been suggested as a treatment for castration-resistant prostate cancer (CRPC). Our aim was to conduct a meta-analysis and indirect comparison to assess the efficacy and safety of ET-A receptor antagonists for treatment of CRPC. METHODS: We systematically searched PubMed, EMBASE, the Cochrane Library, and Web of Science from inception to November 2014 to identify randomized controlled trials (RCTs) which assessed ET-A receptor antagonists for treatment of CRPC. Meta-analysis was conducted by STATA version 12.0 software. RESULTS: Eight RCTs were identified, involving 6,065 patients. The results of direct comparison showed that compared with placebo, there was no statistically significant difference in the improvement of progression-free survival (PFS), overall survival (OS), time to disease progression (TTP), and total adverse events (AEs) with ET-A receptor antagonist treatment for CRPC. The results of ET-A receptor antagonists plus docetaxel versus docetaxel alone were similar. The indirect comparisons showed that there were no significant differences between zibotentan plus docetaxel versus atrasentan plus docetaxel when compared with docetaxel alone or zibotentan versus atrasenta compared with placebo in the improvement of PFS, OS, TTP, and total adverse events. CONCLUSIONS: There were no significant benefits for ET-A receptor antagonists with or without docetaxel in the improvement of PFS, OS, TTP, and overall AEs. And there were no significant differences between zibotentan and atrasentan. Single-agent docetaxel should remain as one of the standard treatments.