Nonclinical Characterization of the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment of Anemia of Chronic Kidney Disease

Balzo, U del; Signore, Pierre; Walkinshaw, Gail; Seeley, Todd W.; Brenner, Mary E.; Wang, Qingjian; Guo, Guangjie; Arend, Michael; Flippin, Lee A.; Chow, F. Aisha; Gervasi, David C.; Kjaergaard, Christian H.; Langsetmo, I.; Guenzler, Volkmar; Liu, David Y.; Klaus, Stephen J.; Lin, Al; Neff, Thomas B.

doi:10.1124/jpet.120.265181

Cited by 47 publications

(47 citation statements)

References 64 publications

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“…To this end we addressed whether PHDi can confirm induction of UCP1 expression as we have seen in the genetic model of adipose-specific PHD2 deletion. PHDi leads to HIF-1a and HIF-2a stabilization in various experimental models and tissues (15,(36)(37)(38) including adipose tissue (15,27). Here, we showed that PHDi increased both protein ( Figure 3a) and mRNA ( Figure 3b) levels of UCP1 in a mouse immortalized BAT cell line (39).…”

Section: Pan-phd Inhibition Induces Ucp1 In Vitro the Unexpected Finmentioning

confidence: 58%

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Gómez

Cervera

Wang

et al. 2021

Preprint

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Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higher Ucp1 mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction of UCP1 mRNA expression by FG2216, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study revealed that serum PHD2 (aka EGLN1) associates with increased risk of metabolic disease. Our data suggest adipose–selective PHD2 inhibition as a novel therapeutic strategy for metabolic disease and identify serum PHD2 as a potential biomarker.

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Section: Pan-phd Inhibition Induces Ucp1 In Vitro the Unexpected Finmentioning

confidence: 58%

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Gómez

Cervera

Wang

et al. 2021

Preprint

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“…127 Comparable erythropoietic effects were seen with JNJ-42905343 (HIF-PHI in preclinical development) and roxadustat in experimental inflammation. 53,134 In addition to proerythropoietic effects, HIF-PHIs have been shown to have anti-inflammatory effects in several disease models, such as acute ischemic injury and sepsis. The underlying mechanisms are complex, highly context dependent, and likely to involve interactions between the HIF pathway and proinflammatory nuclear factor-kB signaling, direct and/or indirect effects of cytokine production, and modulation of innate and adaptive immune responses.…”

Section: Patients With Inflammationmentioning

confidence: 99%

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

Haase

2021

Kidney International Supplements

111

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Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a promising new class of orally administered drugs currently in late-stage global clinical development for the treatment of anemia of chronic kidney disease (CKD). HIF-PHIs activate the HIF oxygen-sensing pathway and are efficacious in correcting and maintaining hemoglobin levels in patients with non-dialysis-and dialysis-dependent CKD. In addition to promoting erythropoiesis through the increase in endogenous erythropoietin production, HIF-PHIs reduce hepcidin levels and modulate iron metabolism, providing increases in total iron binding capacity and transferrin levels, and potentially reducing the need for i.v. iron supplementation. Furthermore, HIF-activating drugs are predicted to have effects that extend beyond erythropoiesis. This review summarizes clinical data from current HIF-PHI trials in patients with anemia of CKD, discusses mechanisms of action and pharmacologic properties of HIF-PHIs, and deliberates over safety concerns and potential impact on anemia management in patients with CKD.

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“…[33][34][35] Roxadustat reversibly stabilizes HIF-a, which promotes a coordinated erythropoietic response by activating a number of genes, including those encoding endogenous erythropoietin, enzymes of heme biosynthesis, and proteins that promote bone marrow iron availability via improved absorption and transport. 35,36 HIF-PH inhibitors are taken orally and routinely self-administered. In phase 2 and smaller, single-nation phase 3 studies among patients with NDD-CKD and anemia, roxadustat increased and maintained Hb levels, [37][38][39] with similar adverse events (AEs) compared with placebo.…”

mentioning

confidence: 99%

Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study

Fishbane

El-Shahawy

Pécoits-Filho

et al. 2021

JASN

124

158

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BackgroundCurrent anemia therapies for patients with non–dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis.MethodsIn this double-blind phase 3 study, we randomized patients with non–dialysis-dependent CKD stages 3–5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28–52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events.ResultsThe study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%).ConclusionsRoxadustat effectively increased hemoglobin in patients with non–dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo.Clinical Trial registry name and registration number:Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627

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Nonclinical Characterization of the Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat, a Novel Treatment of Anemia of Chronic Kidney Disease

Cited by 47 publications

References 64 publications

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality

Hypoxia-inducible factor–prolyl hydroxylase inhibitors in the treatment of anemia of chronic kidney disease

Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study

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