Additional studies about roxadustat, a drug in the new class of hypoxia-inducible factor stabilizers, were released during Kidney Week; one of them explored its role in lowering cholesterol in patients with chronic kidney disease (CKD) and anemia.
Additional research was presented at the American Society of Nephrology Kidney Week about oral roxadustat, which, if approved by the FDA this quarter, would be the first hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) to market to treat anemia in patients with chronic kidney disease (CKD).
HIF-PHI drugs aim to restore production of the hormone erythropoietin and improve iron regulation; currently, the condition is treated by injections of epoetin alpha and darbepoetin alpha.
Roxadustat, for patients both on dialysis and not on dialysis, has a Prescription Drug User Fee Act date of December 20, 2020. It was developed by FibroGen and would be marketed by AstraZeneca. The first set of phase 3 safety and efficacy data was released at least year’s Kidney Week.
Among the many studies the companies released this year, one abstract examined the agent’s effect on low-density lipoprotein cholesterol (LDL).1 In phase 2 studies, roxadustat lowered LDL cholesterol.
Researchers pooled data from 3 phase 3 studies in patients with non–dialysis-dependent (NDD)
NDD-CKD and 3 pivotal phase 3 studies in patients with dialysis-dependent CKD (DD-CKD), including those with incident dialysis (ID), defined as dialysis for less than 4 months.
Patients may or may not have been on statins; mean changes from baseline in LDL-C were averaged over weeks 12 to 28 and analyzed using a mixed model of repeated measures and reported least-squares mean (LSM) treatment differences.
The LSM treatment differences were statistically significant (P < .0001) across all 3 groups:
Roxadustat and congestive heart failure
In the phase 3 trials of roxadustat, researchers also examined congestive heart failure (CHF),2 a common comorbidity in CKD, as it is linked with a worse prognosis. The prevalence increases with CKD severity, ranging from about 20% in mild CKD in patients aged 65 and older to 40% in patients on hemodialysis.
Researchers pooled safety data from the pivotal trials, comparing roxadustat to placebo in stage 3 to 5 NDD-CKD patients, and to epoetin alfa in patients with DD patients, as well as a subgroup of ID-DD.
CHF hospitalization events were a component of the MACE-plus endpoints and analyzed by a Cox proportional hazards regression model; these analyses were not powered for individual components endpoints. Patients with baseline moderate to severe CHF were excluded.
In the pooled NDD studies, 4270 patients were analyzed (2386 roxadustat; 1884 placebo). Baseline CHF history was comparable between roxadustat (13.0%) and placebo (13.6%) arms. Using intent to treat long-term follow-up, the hazard ratio (HR) (95% CI) of hospitalization for CHF among the NDD pooled population was 0.89 (0.72-1.12) for roxadustat vs placebo.
In the pooled DD studies, 3880 patients were analyzed (1940 roxadustat; 1940 epoetin alfa). Baseline CHF history was comparable between roxadustat (25.7%) and epoetin (25.3%) arms, and in the ID-DD subgroup (n = 1526) of 26.4 vs 27.0%, respectively.
Using on-treatment analysis comparing roxadustat with epoetin alfa in the DD studies, the HR (95% CI) of hospitalized CHF was 0.73 (0.58-0.94; P = .013).
In the ID-DD subgroup, the HR (95% CI) was 0.77 (0.42-1.40).
Roxadustat showed a 27% reduction in risk for CHF hospitalization compared with epoetin alfa in the DD population, and a trend based on the point estimates toward reduction of risk compared with placebo in NDD, and to epoetin alfa in ID-DD patients.
Roxadustat and neoplasms
In another study, researchers said they did not find any clinically meaningful between treatment-group differences in neoplasm-related adverse event (AE) and serious adverse event (SAE) rates in the phase 3 clinical trials.3
Roxadustat activates HIF and transcription of HIF-responsive genes, including for erythropoietin.
Looking at pooled data from the 6 pivotal studies, researchers compared AEs/SAEs reported during the treatment period +28 days and +7 days after the last dose of roxadustat.
Patients were excluded if they had a history of malignancy, except for those determined to be cured or in remission for ≥ 5 years, curatively resected basal/squamous cell cancers, cervical cancer in situ, or resected colon polyps.
In the NDD population, 4270 patients were randomized (roxadustat = 2386, placebo = 1884), corresponding to 3870.7 and 2323.2 patient-exposure years (PEY), respectively. Neoplasm-related AE rates were 2.5/100 PEY in both the roxadustat and placebo groups. Neoplasm-related SAE rates were 1.1/100 PEY and 1.3/100 PEY in the roxadustat and placebo groups.
In the DD population, 3880 patients were randomized (roxadustat = 1940, epoetin alfa = 1940), corresponding to 3315.3 and 3743.6 PEY, respectively.
Neoplasm-related AE rates were 2.7/100 PEY and 2.3/100 PEY in the roxadustat and epoetin alfa groups. Neoplasm-related SAE rates were 1.1/100 PEY and 1.2/100 PEY.
In both the NDD- and DD-CKD populations, there were no between treatment-group differences in organ tumors.
1. Roger SD, El-Shahawy MA, Pollock CA, et al. CVD, BP, and kidney diseases: Exploring the link roxadustat lowers low-density lipoprotein cholesterol in patients with anemia of CKD. Presented at American Society of Nephrology Kidney Week. Poster 2113.
2. Provenzano R, Szczech L, Zhong M, et al. Hypertension and vascular disease: From the lab to trials pooled analyses of the phase 3 roxadustat studies: congestive heart failure hospitalization rates in dialysis and non-dialysis patients with anemia treated with roxadustat vs. comparators. Presented at American Society of Nephrology Kidney Week. Abstract SA-OR39.
3. Coyne DW, Fishband S, Pergola PE, et al. Breakthroughs in anemia and iron management roxadustat is not associated with an increased risk of neoplasm in patients with CKD and anemia. Presented at: Presented at American Society of Nephrology Kidney Week. Poster TH-OR04.