MO002OPHTHALMOLOGICAL EFFECTS OF ROXADUSTAT IN THE TREATMENT OF ANAEMIA IN CHRONIC KIDNEY DISEASE PATIENTS ON DIALYSIS IN A PHASE 3, RANDOMISED, DOUBLE-BLIND, ACTIVE-COMPARATOR CONVERSION STUDY

Abstract

Abstract Background and Aims Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved in China for the treatment of dialysis-dependent (DD) and non–dialysis-dependent chronic kidney disease (CKD) anaemia, and in Japan for the treatment of DD CKD anaemia. An acceptable safety profile as well as noninferiority of roxadustat to darbepoetin alfa (DA), measured by haemoglobin (Hb) change from baseline (BL), was shown in patients (pts) with DD CKD in a Japanese phase 3, randomised double-blind, double-dummy study (CL-0307). Some nonclinical data suggest that HIF stimulation may promote angiogenesis, thereby increasing the risk of certain retinal pathologies. As such, this report focuses on a prospective analysis of ophthalmological/retinal-related events observed during the 24-week study period of the aforementioned phase 3 study. Method Japanese pts with DD CKD were randomised 1:1 to receive roxadustat three times weekly or DA once weekly; doses were titrated to maintain Hb between 10–12 g/dL. Ophthalmological/retinal-related outcomes were evaluated in pts who received ≥1 dose of study drug (SAF) and included emergence of adverse events assessed by the investigator and ophthalmological findings based on assessments performed by centralised grading. Ophthalmic imaging (colour fundus photography, optical coherence tomography) and assessment of visual acuity were performed at BL, Week 12, and Week 24 or at study discontinuation according to Ophthalmic Image Acquisition Guidelines. Each investigator evaluated the ophthalmic images and assessed the clinical relevance of any changes. Central evaluation of ophthalmological examination results was then performed by two independent specialists who were blinded to study treatment. During central evaluation, the reviewers assessed ophthalmic images in accordance with the Safety Independent Ophthalmology Review Charter. If graders’ results disagreed, adjudication was performed by a blinded, independent grader who did not participate in the primary review of the patient data. Grading results and visual acuity were analysed descriptively. Results In the SAF, a total of 302 pts were randomised to receive either roxadustat (n=150) or DA (n=152). At BL, previous or concurrent retinal vascular disorders were present in 41.3% (62/150) and 37.5% (57/152) of pts in the roxadustat and DA groups, respectively; 32.7% (49/150) and 27.6% (42/152) of pts presented with a history of both diabetes mellitus and retinal vascular disorders, respectively. The mean (SD) duration of exposure to study drug was 146.7 (45.8) days in the roxadustat group and 154.7 (37.4) days in the DA group. The proportion of pts with new or worsening retinal haemorrhages during the treatment period was 32.4% (n=46/142) with roxadustat and 36.6% (n=53/145) with DA. In a subgroup analysis of pts with no retinal haemorrhage at BL, the proportion of pts with new retinal haemorrhages was 19.1% (n=18/94) with roxadustat and 25.0% (n=24/96) with DA during the treatment period; in pts with ≥1 retinal haemorrhage at BL, the proportion of pts with new or worsening retinal haemorrhages was 58.3% (n=28/48) with roxadustat and 59.2% (n=29/49) with DA during the treatment period. From BL, no clinically meaningful changes in visual acuity or retinal thickness were found in either treatment group. Similarly, from BL, no clinically meaningful changes were found in the proportion of pts exhibiting intra-/sub-retinal fluid, hard exudates, or cotton wool spots in either treatment group. Conclusion These findings suggest that, during the 24-week treatment period, DD CKD pts treated with roxadustat were not at an increased risk of ophthalmic abnormalities—including retinal haemorrhages or increased retinal thickness—compared with pts treated with DA.