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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Erythropoiesis-maturing agents (EMAs), which are specific activin fusion proteins that act as ligand traps to neutralize negative regulators of erythropoiesis, have now been tested in patients with LR-MDS. Luspartercept (ACE-536) has shown ability to increase hemoglobin levels in LR-disease and is approved for patients with beta-thalassemia. The Phase II LR-MDS study reveals 63% erythroid responses with 38% achieving red-cell transfusion independence, particularly in patients with ringed sideroblasts or SF3B1-defined LR-MDS. The study met its primary end-points and is anticipated to be approved in 2020.131 Roxadustat (FG-4592) is an oral hypoxia-inducible factor inhibitor being tested in a Phase III study in LD-MDS in an effort to improve anemia.132 Imetelstat, a telomerase inhibitor, is in a Phase II/III study in red-cell transfusion-dependent and ESA-relapsed/refractory LR-MDS patients. Drugs aimed at improving thrombocytopenia, noted in about 50% of all LR-MDS patients, are also being tested. The TPO-receptor agonists romiplostim and elthrombopag have now been tested in Phase III studies and found to have platelet responses associated with survival benefits but are not approved as yet. Several other novel approaches are being tested, including second-generation HMAs, guadecitabine and ASTX727, and combinations of azacytidine with either lenalidomide, vorinostat (a TPO-receptor agonist), or pevonedistat (an NEDD8-activating enzyme).133 Several combination trials of venetoclax with azacytidine, including those adding tagraxofusp, a CD123-targeted drug, in the untreated and relapsed/refractory setting, and studies of immune checkpoint modulation with HMAs are also in progress. Other candidate approaches include vyxeos (CPX-351), a novel liposomal formulation of cytarabine and daunorubicin recently licensed for secondary AML or tMN, targeted IDH1/2 or FLT3 inhibitors, splicesome-modulator H3B-8800, CAR T-cells, and bispecific antibodies.
Is serum hemoglobin level an independent prognostic factor for IgA nephropathy?: a systematic review and meta-analysis of observational cohort studies
Published in Renal Failure, 2023
Kang Zhang, Meng-di Wang, Shang-shang Jiang, Long Tang, Yue-fen Wang, Yuan Meng, Zhen Cai, Xue-yan Sun, Fang-qiang Cui, Wen-jing Zhao
Although decreased Hb was significantly associated with poor prognosis of IgAN patients, whether early clinical intervention to renal anemia has renoprotective effects remains unknown. In IgAN, renal anemia is mainly caused by decreased erythropoietin (EPO) production [13]. Since 1989, erythropoiesis-stimulating agents (ESAs) have been applied to treat renal anemia [37,38]. ESAs have good curative effects in increasing Hb levels and reducing transfusion requirements. However, a large randomized controlled trial (RCT) conducted in 24 countries showed that in CKD patients who do not rely on dialysis, the use of darbepoetin alfa did not reduce ESRD risk and was associated with an increased risk of stroke [39]. As an inhibitor that specifically suppresses the enzymic activity of hypoxia-inducible factor prolyl hydroxylase enzyme, Roxadustat (FG-4592) has been demonstrated to be non-inferior to ESAs for improving hemoglobin in CKD patients [40,41]. Whether using FG-4592 will influence hard renal endpoints, including ESRD and mortality, remains unknown. Although an experimental study found that the HIF pathway might enhance kidney fibrosis [42], FG-4592 use did not suggest an increased risk of kidney fibrosis [43]. In contrast, in a mice model of ischemia/reperfusion（I/R）-induced acute kidney injury (AKI), FG-4592 protected tubular epithelial cells against hypoxia-induced injury by inhibiting inflammation [44]. Therefore, large RCTs are still needed to investigate whether HIF-PHI therapy at an earlier stage of Hb decline could delay the progression of kidney disease.
Recent applications of click chemistry in drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Xiangyi Jiang, Xia Hao, Lanlan Jing, Gaochan Wu, Dongwei Kang, Xinyong Liu, Peng Zhan
Stabilization of hypoxia-inducing factor-α (HIF-α) is a potent method to stimulate the erythropoiesis [13]. In 2018, based on the structural characteristics of reported compounds 7–9, CuAAC click chemistry was applied to search for HIF prolyl hydroxylase 2 inhibitors, and a set of triazole derivatives was found to display improved inhibitory potency in fluorescence polarization assay. Notably, 10 (IC50 = 62.23 nM) was orally active, and was almost 10 times more potent than FG-4592 (a phase III drug, IC50 = 591.4 nM). Moreover, it can upregulate hemoglobin in cisplatin-induced anemic mice (120 g/L) to normal levels (160 g/L) with low in vivo toxicity (Figure 6) [14]. In short, this work culminated in the discovery of 10 as a clinical candidate for the treatment of renal anemia.
Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against renal ischemia/reperfusion injury by inhibiting inflammation
Published in Renal Failure, 2021
A-Feng Miao, Jian-Xiang Liang, Lei Yao, Jun-Ling Han, Li-Juan Zhou
FG-4592 is a specific small-molecule HIF-PHD inhibitor (HIF-PHI) that is undergoing phase IV trials for the treatment of renal anemia by stimulating HIF activation [8]. Giving that renal HIF system exerts a central role in endogenous defense mechanisms against injury, we speculated that FG-4592 could ameliorate AKI. Moreover, whether FG-4592 can protect against kidney injury via inhibiting inflammation remains unclear. Therefore, in the present study, we studied the effects of FG-4592 on ischemia/reperfusion (I/R)-induced kidney injury, as well as the potential mechanisms.