Background: Chronic kidney disease (CKD) is a known risk factor for stroke that leads to significant long-term disability. Efferocytosis, the process by which microglia engulf and clear apoptotic cells, is essential for stroke recovery. However, its impairment can hinder recovery and worsen the outcomes. Desidustat, an oral hypoxia-inducible factor-prolyl hydroxylase inhibitor, has emerged as a promising treatment for anemia associated with CKD. Despite its clinical potential, its effects on microglial efferocytosis and subsequent effects on stroke recovery have not yet been studied. Objective: To evaluate the mechanistic role of desidustat in mitigating CKD-induced defective microglial efferocytosis and enhancing sensorimotor recovery following embolic stroke. Methods: CKD was induced in adult C57BL/6 mice by oral administration of adenine (50 mg/kg) for 28 days. Acute Ischemic stroke was induced in mice with CKD using an embolic model. Sensorimotor function tests (modified neurological severity score and corner test) were performed for up to 4-weeks post-stroke. Inflammation, apoptosis, and the effect of CKD on microglial efferocytosis following stroke were assessed 72 h post-stroke using in vitro and in vivo functional assays. Desidustat 15 mg/kg was administered orally starting on day 14 of adenine treatment and continued for 28 days post-stroke in mice with CKD. Human-induced microglial cells were used to evaluate the mechanistic role of desidustat in promoting efferocytosis of apoptotic neurons. Results: Mice with CKD exhibited elevated blood urea nitrogen and creatinine levels, accompanied by tubulointerstitial abnormalities and vascular fibrosis in the kidneys. Stroke induction in mice with CKD resulted in increased cerebral inflammation and reduced microglial efferocytosis 72 h post-stroke which was concomitant with worse neurological outcomes and sensorimotor function tests for up to 4 weeks as compared to controls. Desidustat treatment significantly reduced cerebral inflammation and enhanced microglial efferocytosis (72 h post-stroke) and improved neurological recovery and sensorimotor function for up to 4 weeks. In vitro mechanistic studies revealed that desidustat directly enhanced efferocytosis in a human microglial-neuronal co-culture assay. Conclusion: Our results demonstrated that desidustat treatment enhances microglial efferocytosis and improves neurological outcomes and sensorimotor deficits following ischemic stroke in mice.
Background: A phase 3 study to assess the efficacy and safety of the desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, against the epoetin alfa for the treatment of anemia in patients with chronic kidney disease (CKD) with dialysis dependency. Methods: DREAM-D was a phase 3, multicenter, open-label, randomized, active-controlled clinical study conducted across 38 centers in India. A total of 392 patients with clinical diagnosis of anemia due to CKD with dialysis need (Erythrocyte Stimulating Agent [ESA] naïve or prior ESA users) and with baseline hemoglobin levels of 8.0–11.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat oral tablets (thrice a week) or epoetin alfa subcutaneous injection for 24 weeks to maintain a hemoglobin level of 10–12 g/dL. The primary endpoint was to assess the change in the hemoglobin level between the desidustat and the epoetin alfa groups from the baseline to evaluation period week 16–24. The key secondary efficacy endpoint was the number of patients with hemoglobin response. Results: The least square mean (standard error) change in hemoglobin from the baseline to week 16–24 was 0.95 (0.09) g/dL in the desidustat group and 0.80 (0.09) g/dL in the epoetin alfa group (difference: 0.14 [0.14] g/dL; 95% confidence interval: −0.1304, 0.4202), which met the prespecified noninferiority margin. The number of hemoglobin responders was significantly higher in the desidustat group (106 [59.22%]) when compared to the epoetin alfa group (89 [48.37%]) (p = 0.0382). The safety profile of the desidustat oral tablet was comparable with the epoetin alfa injection. There were no new risks or no increased risks seen with the use of desidustat compared to epoetin alfa. Conclusion: In this study, desidustat was found to be noninferior to epoetin in the treatment of anemia in CKD patients on dialysis and it was well-tolerated. Clinical Trial Registry Identifier: CTRI/2019/12/022312 (India).
Many anemic chronic kidney disease (CKD) patients are refractory to erythropoietin (EPO) effects due to inflammation, deranged iron utilization, and generation of EPO antibodies. This work assessed the effect of desidustat, an inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase (PHD), on EPO-refractory renal anemia. Sprague Dawley rats were made anemic by cisplatin (5 mg/kg, IP, single dose) and turpentine oil (5 mL/kg, SC, once a week). These rats were given recombinant human EPO (rhEPO, 1 μg/kg) and desidustat (15 or 30 mg/kg) for eight weeks. Separately, rhEPO (1–5 μg/kg) was given to anemic rats to sustain the normal hemoglobin levels and desidustat (15 mg/kg) for eight weeks. In another experiment, the anemic rats were treated rhEPO (5 μg/kg) for two weeks and then desidustat (15 mg/kg) for the next two weeks. Dosing of rhEPO was thrice a week, and for desidustat, it was on alternate days. Desidustat inhibited EPO-resistance caused by rhEPO treatment, decreased hepcidin, IL-6, IL-1β, and increased iron and liver ferroportin. Desidustat reduced EPO requirement and anti-EPO antibodies. Desidustat also maintained normal hemoglobin levels after cessation of rhEPO treatment. Thus, novel prolyl hydroxylase inhibitor desidustat can treat EPO resistance via improved iron utilization and decreased inflammation.
Vaccines remain the key protective measure to achieve herd immunity to control the disease burden and stop COVID-19 pandemic. We have developed and assessed the immunogenicity and protective efficacy of two formulations (1mg and 2mg) of ZyCoV-D (a plasmid DNA based vaccine candidates) administered through Needle Free Injection System (NFIS) and syringe-needle (intradermal) in rhesus macaques with three dose vaccine regimens. The vaccine candidate 2mg dose administered using Needle Free Injection System (NFIS) elicited a significant immune response with development of SARS-CoV-2 S1 spike region specific IgG and neutralizing antibody (NAb) titers during the immunization phase and significant enhancement in the levels after the virus challenge. In 2 mg NFIS group the IgG and NAb titers were maintained and showed gradual rise during the immunization period (15 weeks) and till 2 weeks after the virus challenge. It also conferred better protection to macaques evident by the viral clearance from nasal swab, throat swab and bronchoalveolar lavage fluid specimens in comparison with macaques from other immunized groups. In contrast, the animals from placebo group developed high levels of viremia and lung disease following the virus challenge. Besides this, the vaccine candidate also induced increase lymphocyte proliferation and cytokines response (IL-6, IL-5).The administration of the vaccine candidate with NFIS generated a better immunogenicity response in comparison to syringe-needle (intradermal route). The study demonstrated immunogenicity and protective efficacy of the vaccine candidate, ZyCoV-D in rhesus macaques.
Forced degradation study is a systemic characterization of degradation products of active pharmaceutical ingredient (API) at conditions which posses more harsh environment that accelerates degradation of API. Forced degradation and stability studies would be useful in selection of proper, packaging material and storage conditions of the API. These are also useful to demonstrate degradation pathways and degradation products of the API and further characterisation of the degradation products using mass spectrometry. TGR5 is a G protein-coupled receptor, activation of which promotes secretion of glucagon-like peptide-1 (GLP-1) and modulates insulin secretion. The potent and orally bioavailable TGR5 agonist, ZY12201, shows activation of TGR5 which increase secretion of GLP-1 and help in lowering blood glucose level in animal models. Hence it is necessary to establish and study degradation pathway and stability of API for better handling and regulatory approval. Force degradation studies of ZY12201 have shown presence of one oxidative impurity during oxidative degradation in HPLC analysis. The oxidized product is further characterized by LC-MS to elucidate structure of impurity and characterize its degradation pathway.
