Management of Anemia in Non-Dialysis-Dependent (NDD) and HD CKD Patients
Studies 1 and 2: 0.5, 2, and 5 mg
Two parallel phase IIA randomized, blinded, controlled studies were conducted with daprodustat over a 4-week time period in separate populations with CKD to evaluate the safety and efficacy of daprodustat . The first study, referred to as the ‘Nondialysis Study’, was conducted in patients with CKD stages 3–5 not undergoing dialysis who had not used recombinant human erythropoietin (rhEPO) within the past 7 weeks. The second study, referred to as the ‘Hemodialysis Study’, was conducted in patients receiving hemodialysis three times weekly and adequately responded to rhEPO treatment. Per the protocol, patients would be withdrawn from the studies if their hemoglobin was < 8.0, > 13.0 g/dL, or they experienced a change of 2.0 g/dL in a 1-week time period. Patients were randomized 1:1:1:1 in each study with the active treatment being one of three doses of daprodustat, 0.5, 2, or 5 mg. Placebo was used in the nondialysis study while maintenance of current rhEPO therapy was used as the control arm in the HDD study.
Seventy-three patients were randomized in the NDD study, of which 59 (81%) had completed the study through follow-up at weeks 6 and 54 . One-hundred percent of the NDD patients had cardiovascular risk factors at baseline, including hypertension (97%), hyperlipidemia (76%), and diabetes (69%). In the HDD study, 83 patients were randomized, of which 70 (84%) patients completed the study through follow-up. Similarly, 95% of the dialysis participants had cardiovascular risk factors including hypertension (95%), hyperlipidemia (57%), and diabetes (45%). Over the 4-week treatment period in the NDD study, the mean observed change from baseline (CFB) in hemoglobin for the 0.5, 2, and 5 mg doses of daprodustat were − 0.121, 0.121, and 0.951 g/dL respectively, compared to − 0.15 g/dL in the placebo arm. In the HDD study, CFB in Hb for doses of 0.5, 2, and 5 mg of daprodustat were − 1.06, − 0.93, and − 0.08 g/dL respectively compared to − 0.25 g/dL in the active control arm. EPO concentrations did not accumulate over the treatment period with daprodustat. Comparing the median peak EPO concentrations across the groups in the HDD study, the results were 424.9, 13.9, 12.7, and 24.7 U/L for the rhEPO 0.5, 2, and 5 mg of daprodustat groups, respectively. There were no clinically relevant changes in plasma VEGF in either daprodustat studies. The pharmacodynamic assessments were limited to 11 h post-dose, and thus the true peak plasma concentrations of EPO and VEGF may not have been captured. Five AEs were reported for one or more participants receiving daprodustat: two experienced nausea in the nondialysis study and three experienced anemia in the HDD study. However, drug-related adverse events were not clearly distinguished in these studies. While no deaths occurred in either study, two serious adverse events (SAEs) were reported post-therapy in the HDD study for patients receiving 0.5 mg of daprodustat, which included an abnormal liver function test and acute respiratory failure.
Study 3: 10, 25, 50, and 100 mg
A phase IIA, randomized, placebo-controlled, dose ranging study of daprodustat was conducted in anemic patients (Hb ≤ 11.0 g/dL) with CKD . Participants were grouped separately according to their degree of renal impairment; that is, either NDD-CKD stages 3–5 or hemodialysis-dependent CKD stage 5 (corresponding eGFR: 15–59 mL/min/1.73 m2 for stages 3–4; 10 to < 15 mL/min/1.73 m2 for stage 5). The study evaluated safety and tolerability end points as well as collected PK/PD data for once-daily administration of daprodustat over a period of 28 days with post-treatment follow-up to day 57. Participants were enrolled to receive doses of 10, 25, 50, and 100 mg in the NDD group and doses of 10 and 25 mg in the HD group. A total of 107 participants, predominantly white females and patients of Asian descent, were enrolled in this study. Seventy patients were randomized to the NDD group and 37 were randomized to the HD group.
A priori response rates were defined as a Hb level increase of 1.0 and 0.5 g/dL . The percentage of patients achieving these response were 63 and 91% for the NDD group and 71 and 89% for the HD group. Per the protocol-defined safety criteria, dosing in any treatment arm would be stopped if the Hb level was > 13.5 g/dL or the rate of Hb level increase was > 1 g/dL over a 2-week period. Combined, the number of patients that experienced a rapid increase in Hb level and subsequent study withdrawal was 21 of 70 (30%) and 8 of 37 (22%) for the NDD and HD groups, respectively. Accounting for all reasons for withdrawal, only 30 participants in the NDD group and 22 participants in the HD group receiving daprodustat completed the study. With respect to the safety of daprodustat, 35 of 61 patients with NDD-CKD and 15 of 31 patients with HD-CKD experienced AEs, of which 16 were considered by the investigator to be drug-related. Nausea was the most common drug-related AE in the NDD group, with 5 of the 6 events occurring with those receiving the 100 mg dose. While no deaths were reported in the study, 2 of 7 participants reported SAEs in the NDD group occurred in patients receiving 100-mg doses and were considered to be related to the study drug. None of the reported SAEs for the 3 participants in the HD group were considered to be related to daprodustat.
Management of Anemia in Hemodialysis (HD) Patients: 4, 6, 8, and 10 mg
A phase II, randomized, placebo-controlled, dose ranging study of daprodustat was conducted in Japanese patients on HD in response to variabilities in a PK analysis in a previous phase I trial . This study sought to evaluate the Hb dose response and the safety of daprodustat in Japanese patients [13, 16]. The study randomized 97 Japanese patients who had been on HD for ≥ 8 weeks and who were effectively managed with an ESA resulting in stable Hb levels. Patients discontinued their ESA for 2–8 weeks prior to enrollment and were eligible for inclusion if they had a decrease in Hb of ≥ 0.5 g/dL with a resulting baseline of 8.5–10 g/dL. Patients were randomized 1:1:1:1:1 to receive 4, 6, 8, 10 mg of daprodustat or placebo daily. Eighty-nine percent of patients completed the trial with the mean baseline Hb ranging from 9.68 to 9.92 g/dL. The primary endpoint of change in Hb levels at week 4 was − 0.28, − 0.01, 0.54, and 0.97 in the 4, 6, 8, and 10 mg groups, respectively, compared to a decrease of − 1.41 g/dL in the placebo arm. Changes in other blood parameters such as RBC and reticulocytes were consistent with the changes in Hb. Plasma EPO concentrations increased in a dose-related manner up to 8 mg, with no additional increases with 10 mg. HIF-1 upregulates VEGF, which is implicated in angiogenic activity, tumor growth, and macular edema. VEGF levels were also measured and there were no significant differences observed between any of the groups.
Other secondary endpoints included iron parameters . Totals of 5 and 20% of participants received stable oral or IV iron supplementation, respectively, throughout the study. There was a dose-dependent decrease in hepcidin and ferritin coupled with increases in transferrin and TIBC, indicating a dose–response relationship with increased iron utilization. Modest decreases in lipid levels were seen at week 4 in the daprodustat arm, and there was a higher incidence of nasopharyngitis in participants who received daprodustat compared to placebo.