Positive results from three phase III studies of roxadustat for anemia in patients with chronic kidney disease. FibroGen + AstraZeneca

FibroGen, Inc. announced that roxadustat, an inhibitor of hypoxia-inducible-factor (HIF) prolyl hydroxylase activity (HIF-PHI), met all primary efficacy endpoints in the three global pivotal Phase III trials conducted by FibroGen. That is, ANDES in non-dialysis-dependent (NDD) chronic kidney disease (CKD) patients, HIMALAYAS in incident (newly initiated) dialysis patients, and SIERRAS in dialysis-dependent (DD) CKD patients. Each of the three studies had a pre-specified primary efficacy endpoint for meeting U.S. regulatory requirements and another pre-specified primary efficacy endpoint for meeting EU regulatory requirements, which also served as a secondary efficacy endpoint for the U.S. Both the U.S. and EU primary efficacy endpoints were met in all three studies.

Non-Dialysis CKD Patients Study (ANDES1): ANDES is a 922-patient global Phase III, randomized, double-blinded, placebo-controlled trial designed to evaluate the efficacy and safety of roxadustat versus placebo for the treatment of anemia in patients with later-stage CKD (stages 3, 4 or 5) who are not dialysis-dependent. This study was conducted in the U.S. and 14 other countries. Treatment duration was up to 4.5 years, with average duration of 1.7 years. Baseline hemoglobin (Hb) levels averaged 9.1 g/dL in both the roxadustat (N=616) and the placebo (N=306) arms. U.S. primary efficacy endpoint: Roxadustat was superior to placebo in mean Hb change from baseline to the average over Weeks 28-52 (2.00 vs 0.16 g/dL, respectively, p<0.0001). eu primary efficacy endpoint: a higher proportion of roxadustat-treated patients (86.0%) achieved a hb response in the first 24 weeks (defined as achieving a hb level of at least 11 g dl and a hb increase of at least 1 g dl) as compared to placebo (6.6%), p="0.0007." furthermore, in a pre-specified secondary efficacy analysis, roxadustat reduced the risk of rescue therapy by 81% (hazard ratio (hr)="0.19)" defined as the time to first use of blood transfusion, administration of an erythropoiesis stimulating agent (esa) or iv iron in the first 52 weeks of treatment, p><0.0001. in addition, roxadustat reduced the risk of blood transfusion by 74% (hr="0.26)" in the time to first blood transfusion during the first 52 weeks of treatment, p><0.0001.>

Incident Dialysis CKD Patients Study (HIMALAYAS2): HIMALAYAS is a 1,043-patient global Phase III randomized, open-label, active-controlled trial to assess the efficacy and safety of roxadustat compared to epoetin alfa, an ESA, for the treatment of anemia in CKD patients who have newly initiated dialysis treatment for end stage renal disease and have had minimal or no exposure to ESA prior to study participation. This study was conducted in the U.S. and 17 other countries. Treatment duration was up to 4.4 years, with mean duration of 1.8 years. Mean baseline Hb was 8.43 g/dL in the roxadustat arm (N=522) and 8.46 g/dL in the epoetin alfa arm (N=521). U.S. primary efficacy endpoint: The mean Hb change from baseline to the average over Weeks 28-52 was 2.57 g/dL (roxadustat) vs. 2.36 g/dL (epoetin alfa), a least squares mean difference of 0.18 g/dL, with the 95% confidence interval (CI) of (0.08, 0.29). The non-inferiority criteria was met as the lower bound of the 95% CI was well above the non-inferiority margin of -0.75 g/dL, and superiority over epoetin alfa was also achieved, p=0.0005. EU primary efficacy endpoint: Roxadustat met the non-inferiority criteria compared to epoetin alfa: 88.2% of the roxadustat-treated patients achieved a Hb response in the first 24 weeks (defined as achieving a Hb level of at least 11 g/dL and a Hb increase of at least 1 g/dL) compared to an 84.5% responder rate in the epoetin alfa arm; lower bound of the 95% CI (-0.9%, 7.6%) of the treatment difference in responder rate is well above the non-inferiority margin of -15%.

Stable Dialysis CKD Patients Study (SIERRAS3): SIERRAS is a 741-patient U.S. Phase III, randomized, open-label, active-controlled trial to assess the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia (in maintaining Hb level) in DD-CKD patients who were receiving stable doses of ESA prior to study participation.3 Treatment duration was up to 3.5 years, with a mean duration of 1.9 years. Mean baseline Hb levels were 10.3 g/dL in both roxadustat and epoetin alfa arms. U.S. primary efficacy endpoint: The mean Hb change from baseline to the average over Weeks 28-52 was 0.39 g/dL (roxadustat) vs -0.09 g/dL (epoetin alfa), a least squares mean treatment difference of 0.48 g/dL (95% CI 0.37, 0.59). Roxadustat met the non-inferiority criteria as the lower bound of 95% CI was well above the non-inferiority margin of ?�0.75 g/dL. Roxadustat also achieved superiority, p<0.0001. eu primary efficacy endpoint: the mean hb change from baseline to the average over weeks 28-36 was 0.54 g dl (roxadustat) vs -0.02 g dl (epoetin alfa), a least squares mean treatment difference of 0.53 g dl with a 95% ci (0.39, 0.67). roxadustat met the non-inferiority criteria as the lower bound of the 95% ci was well above the non-inferiority margin of -0.75 g dl. roxadustat also achieved superiority over epoetin alfa, p><0.0001. in addition, in the pre-specified secondary efficacy analysis, roxadustat-treated patients had a 33% reduction in the risk of blood transfusion compared to epoetin alfa (hr="0.67)" in the time to first blood transfusion during treatment, p="0.0337.">

The preliminary safety analyses of each of these three individual studies show an overall safety profile consistent with the results observed in prior roxadustat studies. The adverse events reported are consistent with those expected in these study populations with similar background diseases. These three Phase III studies sponsored and conducted by FibroGen are part of FibroGen�s co-development collaboration with AstraZeneca AB and with Astellas Pharma Inc. These studies are part of the roxadustat global Phases III program, which consists of multiple global studies in more than 50 countries. Results of the pooled safety analyses, including the major adverse cardiovascular events (MACE) for both NDD-CKD and DD-CKD in the global Phase III program is anticipated prior to U.S. NDA submission in the first half of 2019.