Roxadustat: First-in-class safe and effective oral small molecule for CKD-induced anaemia
First-in-class oral small molecule for CKD-induced anaemia
The oxygen-sensing mechanism in the kidney is driven by HIF, a transcription factor that regulates the expression of genes involved in erythropoiesis. Under conditions of normal oxygen tension, the α subunit of HIF is hydroxylated by specific PHs and targeted for rapid proteasomal degradation by the von Hippel-Lindau (VHL) tumour suppressor. Normally, in a hypoxic environment, PH enzyme activity is suppressed, allowing HIF-α to accumulate and translocate to the cell nucleus, where it dimerizes with the HIF-β subunit, forming the functional HIF heterodimer, which activates the transcription of a number of genes, including divalent metal transporter 1 (DMT1), transferrin, transferrin receptor, erythropoietin and erythropoietin receptor genes. [Kidney Int 2006;69:1302-1307] However, in case of pseudonormoxia PH enzymes continue to target HIF-α for degradation despite hypoxic environment.
Roxadustat reversibly binds to and inhibits PH enzymes, leading to rapid and reversible stabilization of HIF-α, promoting HIF activity and causing an increase in endogenous erythropoietin production, thereby enhancing erythropoiesis. (Figure 1) In addition, roxadustat reduces the expression of the peptide hormone hepcidin, which in turn improves iron availability and increases haemoglobin (Hb) levels. [Drugs 2019;79:563-572]
ROCKIES: Roxadustat effective in DD patients
The phase III, international, open-label ROCKIES trial randomized 2,133 CKD [CH5] patients (mean age, 54.0 years; 59 percent male) on dialysis to assess the efficacy and safety of thrice-weekly oral roxadustat (n=1,068) vs an active control agent, parenteral epoetin alfa (n=1,065). [Fishbane S, et al, ASN 2019, abstract TH-OR022]
Roxadustat met the primary efficacy endpoint of greater Hb change from baseline (BL) to average Hb in weeks 28 to 52 vs epoetin alfa (adjusted least squares mean [aLSM] change, +0.77 g/dL vs +0.68 g/dL; p=0.036). The proportion of total time during which Hb was maintained at ≥10 g/dL between weeks 28 and 52 was greater for patients on roxadustat vs epoetin (79 percent vs 76 percent; p=0.045).
“Roxadustat also increased Hb to a greater degree than epoetin alfa [aLSM change, 0.80 g/dL vs 0.59 g/dL; p=0.12] in patients with inflammation, namely those with high-sensitivity C-reactive protein [hsCRP] levels over 5 mg/L, who represent a population historically difficult to treat with epoetin alfa,” said Fishbane.
“Compared with epoetin alfa, roxadustat showed a significantly greater decrease in hepcidin [aLSM change, -44.99 ng/mL vs -16.77 ng/mL; p<0.001], the master regulator of iron status, while also producing a more substantial decrease in ferritin [aLSM change, -104.47 µg/L vs -41.18 µg/L; p<0.001],” reported Fishbane. “With a decrease in storage iron [ferritin] comes an increase in the iron available to make red blood cells [RBCs] and higher serum iron.”
Roxadustat-treated patients saw an aLSM change in serum iron of +6.58 µg/dL, compared with -5.54 µg/dL in the epoetin alfa group. “Average monthly intravenous [IV] iron use was 35 percent lower in patients on roxadustat compared with those on epoetin alfa [59 mg vs 91 mg; p<0.001],” noted Fishbane.
OLYMPUS: Roxadustat effective in NDD patients
OLYMPUS, a phase III, international, double-blind trial randomized 2,781 [CH6] NDD patients with CKD (mean age, 61.7 years; 52 percent male) to roxadustat (n=1,393) or placebo (n=1,388). The patients had a mean Hb of 9.1 g/dL and estimated glomerular filtration rate (eGFR) of 19.8 mL/min/1.73 m2. [Fishbane S, et al, ASN 2019, abstract TH-OR023]
Roxadustat met the primary efficacy endpoint of greater Hb change from BL to average Hb in weeks 28 to 52 vs placebo (aLSM change, +1.75 g/dL vs +0.4 g/dL; p<0.001) in NDD patients.[NR7] The proportion of patients achieving Hb response (defined as Hb ≥11 g/dL or Hb increase >1.0 g/dL if BL Hb was >8 g/dL or Hb increase ≥2 g/dL if BL Hb was ≤8 g/dL) was significantly greater in the roxadustat group vs placebo (77.0 percent vs 8.5 percent; p<0.001).
“Roxadustat achieved a similarly elevated Hb response vs placebo, regardless of patients’ iron repletion status [iron-replete patients: aLSM change, +1.71 g/dL vs +0.39 g/dL; p<0.001; non–iron-replete patients: aLSM change, +1.76 g/dL vs +0.43 g/dL; p<0.001]. In addition, roxadustat demonstrated comparable efficacy in the traditionally hyporesponsive population of patients with elevated hsCRP [aLSM change, +1.73 g/dL vs 0.62 g/dL],” reported Fishbane.
The need for rescue therapy was significantly reduced with roxadustat vs placebo. “The risk of requiring a RBC transfusion decreased by 63 percent in patients on roxadustat [hazard ratio (HR), 0.37; 95 percent confidence interval (CI), 0.30 to 0.44; p<0.001], while the risk of needing IV iron was 59 percent lower in the roxadustat group [HR, 0.41; 95 percent CI, 0.29 to 0.56; p<0.001] and the risk of requiring rescue with an erythropoietin analogue was down by 87 percent [HR, 0.13; 95 percent CI, 010 to 0.18; p<0.001],” said Fishbane.
Pooled analyses of roxadustat’s efficacy and safety
Pooled analyses were conducted to assess roxadustat’s efficacy and safety across six phase III clinical trials, encompassing a total of 4,277 NDD patients (OLYMPUS, ANDES, ALPS trials) with a combined exposure of 6,194 patient-years and a total of 3,880 DD patients (ROCKIES, SIERRAS, HIMALAYS trials) with a combined exposure of 7,059 patient-years. [Provenzano R, et al, ASN 2019, FR-OR131]
“The roxadustat NDD programme included patients who were not studied in prior CKD anaemia trials; 42 percent of patients had an eGFR of <15 mL/min/1.73 m2 and 40 percent of patients had a transferrin saturation [TSAT] of <20 percent,” highlighted Provenzano.
The programme also included 1,530 Incident Dialysis (ID) patients as a clinically relevant subgroup of the DD pool. ID patients typically commence anaemia therapy at the start of dialysis, thus representing the highest-risk group within the DD population.
The primary efficacy endpoint of mean Hb change from BL to weeks 28 to 52 was met in the individual studies of NDD and DD patients, as well as in the pooled analyses. (Figure 2) The change was superior for NDD patients receiving roxadustat vs placebo and was independent of iron repletion status (iron-replete patients: 1.94 g/dL vs 0.13 g/dL; p<0.001; non–iron-replete patients: 1.94 g/dL vs 0.33; p<0.001).
“Roxadustat achieved a higher Hb increase than epoetin alfa in DD patients with or without inflammation [patients with hsCRP >5 mg/L: 1.29 g/dL vs 0.96; p<0.0001; patients with hsCRP ≤5 mg/L: 1.27 g/dL vs 1.05; p<0.0001],” said Provenzano. “DD patients on roxadustat also required less monthly IV iron to maintain the Hb levels than those on epoetin alfa.”
Roxadustat also lowered the use of rescue therapies in NDD patients, such that only 8.9 percent of patients on roxadustat required RBC transfusions, erythropoiesis-stimulating agents or IV iron in the first 52 weeks of treatment vs 31.1 percent of patients on placebo (HR, 0.19; 95 percent CI, 0.16 to 0.23; p<0.001). Specifically, RBC transfusions were required by 5.2 percent of roxadustat-treated NDD patients vs 15.4 percent of patients on placebo (HR, 0.26; 95 percent CI, 0.21 to 0.32; p<0.001). In the DD population, 9.5 percent of patients on roxadustat vs 12.8 percent of patients treated with epoetin alfa received RBC transfusions (HR, 0.82; 95 percent CI, 0.679 to 0.997; p=0.046).
“Roxadustat demonstrated additional treatment benefits in the NDD group,” said Provenzano. “Patients with BL eGFR ≥15 mL/min/1.73m2 who were treated with roxadustat had a mean change in eGFR from BL that was 1.6 mL/min/1.73m2 greater than with placebo [p<0.001], suggesting a significant benefit in preserving renal function. In addition, NDD patients on roxadustat had a mean LDL that was 19.83 mg/dL lower than that of patients receiving placebo [p<0.001].”
“The risk of major adverse cardiovascular events [MACE], MACE+ [MACE, unstable angina requiring hospitalization and congestive heart failure requiring hospitalization], and all-cause mortality was comparable and virtually identical for NDD patients receiving roxadustat or placebo, with HRs of 1.08, 1.04, and 1.06, respectively,” reported Provenzano. “In the DD pool, the risk of MACE [HR, 0.96] and all-cause mortality [HR, 0.96] was not increased with roxadustat compared with epoetin alfa, while there was a significantly lower risk of MACE+ in the roxadustat group [HR, 0.86; p=0.028].” (Figure 3)
In the ID subgroup, roxadustat had a 30 percent lower risk of MACE and a 34 percent lower risk of MACE+ , as well as demonstrating a trend towards lower all-cause mortality vs epoetin alfa.
Roxadustat is a first-in-class oral small-molecule inhibitor of HIF-PH, which effectively and safely boosts Hb levels and lowers the risk of RBC transfusion in NDD and DD patients with CKD-induced anaemia, as demonstrated by individual studies and pooled analyses. It is currently approved for use in NDD and DD patients in China and in DD patients in Japan.