Thank you, Jim. Last week, FibroGen and our partners presented roxadustat Phase III results at the Annual American Society of Nephrology Meeting, which included over 13,000 kidney professionals.
As the nephrologists share our excitement of a potential game changer in anemia therapy based on strong scientific foundation. Today, I would like to review the highlights.
The pooled analyses included data from 6 Phase III trials, including over 8,000 patients and encompass over 13,000 patient exposure years.
Our studies evaluated 3 patient populations; nondialysis-dependent, dialysis-dependent and incident dialysis, which is a subgroup of patients recently started dialysis within 4 months of study's participation. We reported on results of the following safety endpoints; major adverse cardiovascular events or MACE endpoints consists of death due to all causes, nonfatal myocardial infarction and nonfatal stroke; MACE+ consists of the 3 MACE events plus hospitalization due to heart failure or unstable angina, all-cause mortality is simply all death due to any cause.
To maintain objectivity and consistency, the events in these cardiovascular endpoints were adjudicated by independent adjudicators blinded to treatment assignment. The time-to-event analyses are conducted based on pooling strategy and analytical approaches agreed with the FDA and the time to MACE is the primary safety endpoint in the U.S., supported by results of MACE+, which is recognized as an important endpoint in the nephrology community.
In nondialysis, where roxadustat was compared to placebo, which is the gold standard in safety assessment, roxadustat was comparable to placebo in MACE and MACE+ risk using a commonly applied noninferiority margin of 1.3. In dialysis patients, roxadustat reduced the risk of MACE+ by 14% compared to epoetin alfa and had no increased risk of MACE compared to EPO using a commonly applied NI margin of 1.3.
In incident dialysis, roxadustat had a 30% lower risk of MACE and a 34% lower risk of MACE+ than EPO.
Let's discuss the rest of the efficacy and safety results, starting with nondialysis. 4,270-plus CKD patients were enrolled into the 3 Phase III nondialysis studies comparing roxadusat to placebo. In these studies, we included CKD stage 3, 4 and 5 patients. Of whom 42% were CKD stage 5. Their anemia tends to be more severe with their more advanced chronic kidney disease, and they have been generally excluded from prior large CKD anemia studies of ESAs. Similarly, we included patients with a range of iron stores with 40% of study patients non-iron replete at baseline, and thus, they were ineligible for ESA treatment, based on the current ESA label.
Roxadustat met the primary efficacy endpoint of mean change from baseline to average hemoglobin over weeks 28 to 52, in which -- I'm sorry, in each of the 3 individual Phase III studies and in the pooled analyses in which roxadustat was superior to placebo regardless of CKD severity, regardless of severity of anemia at baseline and regardless of iron repletion status. Roxadustat's efficacy is accompanied by an 81% risk reduction in use of rescue treatment, which includes IV iron, ESA and transfusion and a 74% reduction in the risk of red blood cell transfusion, with p-value of 0.001, p-value less than.
Importantly, in comparison to placebo, roxadustat patients also show a slower decline in eGFR, which is a measure of kidney function. Patients with base -- in patients with baseline eGFR of 15 or higher during the first year of treatment.
The one year decline in eGFR in roxa patients was 2.8, which is significantly less than the decline in placebo patients of 4.4 with a treatment difference of 1.6 and p-value has been 0 in that.
This represents a 38% reduction in eGFR decline relative to placebo.
Turning to cardiovascular safety. In the CKD nondialysis pool based on ITT analysis, roxadustat was comparable to placebo.
For reference, here are the hazard ratios. MACE hazard ratio of 1.08 with 95% confidence interval of 0.94 and 1.24, MACE+ has a ratio of 1.04 confidence interval of 0.91 and 1.18, all-cause mortality has a ratio of 1.06, with confidence interval of 0.91 and 1.23.
We have received questions on the individual components of cardiovascular composite endpoint in nondialysis with the most interest in stroke. Well, this is most likely because of the TREAT study on that darbepoetin resulted in the ESA label restriction in its use in nondialysis and dialysis patients. I want to be clear from the outset. We believe the data from the individual components of MACE and MACE+ in the roxadustat program are consistent with the results in the overall analyses. Stated another way, we believe the results in the individual components are comparable to placebo in nondialysis. This is also true for the dialysis pool.
Before we dive into details, I want to remind you that the roxadustat nondialysis program was power for assessing the MACE composite endpoint and not the individual components.
To give a sense of magnitude, in the roxadustat program, stroke represents only 10% of the MACE events in the nondialysis pool and the incidence of rate in roxadustat is comparable to placebo, which is 1.2 per 100 patient years in roxadustat versus 1.1 in placebo arm. Hazard ratio of 1.22, with 95% confidence interval of 0.80 and 1.86.
As a reminder, in the TREAT study the incident rate of stroke in darbepoetin was twice that of placebo, with hazard ratio of 1.92 and 95% confidence interval of 1.38 and 2.18. The rest of the MACE+ component in our nondialysis pool is as follows. All-cause mortality has a ratio of 1.06, confidence interval of 0.91 and 1.23, which we stated earlier. MI has a ratio of 1.28, confidence interval of 0.9 and 1.84 and stable angina requiring hospitalization with hazard ratio of 0.49 and confidence interval of 0.19 and 1.27.
Finally, congestive heart failure requiring hospitalization, which is important in CKD patients has hazard ratio of 0.89, confidence interval of 0.72 and 1.12.
Based on the composite endpoints of time to MACE, MACE+, all-cause mortality and the individual components, the overall cardiovascular safety of roxadustat is comparable to placebo. The dialysis-dependent patient pool consists of 180 patients who were randomized one-to-one to receive roxadustat or epoetin alfa in 3 dialysis Phase III studies. The primary efficacy endpoint of mean change in hemoglobin from baseline to week 28 to 52 was met in each individual study and in the pooled analyses. Roxadustat achieved higher hemoglobin level than active comparator of epoetin alfa. This result was seen in patients with or without inflammation as measured by CRP with similar roxadustat dose requirements regardless of inflammation status with roxadustat treated patients receiving less IV iron than EPO patients.
While transferrin saturation or TSAT, a measure of iron store in the body were comparable between the 2 treatment arms.
In addition, when compared with EPO, roxadustat-treated patients had a lower red blood cell transfusion risk than EPO-treated patients. Hazard ratio of 0.82, p-value of 0.046. The combination of findings above reflects the benefits of coordinated erythropoiesis with roxadustat as treatment resulted in more efficient iron utilization, lower transfusion requirement and can potentially overcome ESA hyporesponsiveness.
Turning to cardiovascular endpoint analysis of the dialysis pool. In MACE and in all-cause mortality, roxadustat had no increased risk relative to EPO. In MACE+, roxadustat had a 14% reduction in risk compared to EPO. I would like to point out the incidence rate of each of the individual MACE+ components in dialysis are numerically lower in roxadustat than EPO.
Finally, let's talk about the exciting patient population, incident dialysis, which is a pre-specified subgroup of the dialysis-dependent pool.
Here, we studied 1,526 new dialysis patients who commenced treatment within 4 months before study participation and were treated up to three years with an average treatment duration of 1.5 year. In the incident dialysis pool, in comparison to epoetin alfa, roxadustat treatment resulted in a 30% reduction in the risk of MACE and a 34% reduction in the risk of MACE+ would trend for lower risk of death. These results suggest potential long-term safety benefits in selecting roxadustat when initiating anemia therapy in dialysis patients.
To evaluate the merits of roxadustat, it is important to put together an overall picture, taking into account efficacy and safety and ask if this drug has the potential to improve anemia treatment in CKD patients.
Our answer is, yes. In nondialysis, our Phase III program show roxadustat treatment corrected anemia effectively regardless of iron repletion and reduced risk of large scale use of blood transfusion while also slowing down the decline in kidney function in patients with EGFR greater than or equal to 15, while MACE,MACE+ and all-cause mortality risk were comparable to placebo, the gold standard.
Because of the safety-related treatment restriction of ESA, coupled with the iron repletion requirement and the inconvenience of parenteral administration requirements, currently there is little use of ESA in nondialysis patients, as USRDS reported that only 15% of patients entering dialysis had received prior ESA treatment. If approved, roxadusat could deliver the therapeutic benefits with the convenience of a pill, unlike ESA, which requires frequent injections at the doctor's office.
In addition to the favorable efficacy and safety characteristics, the convenient dosing of oral medication and removal of the financial and time burden from patients need to stock and inject the medicine, we believe roxadustat has the potential to improve treatment access and patient compliance. Therefore, we believe we have an unprecedented opportunity to expand anemia therapy to the millions of nondialysis patients whose anemia go unaddressed.
In dialysis, currently, the decision on the choice of anemia agent is generally made at the early periods of dialysis treatment. With a 30% reduction in MACE risk and a 34% reduction in MACE+ risk compared with epoetin alfa in incident dialysis patients, we believe roxadustat could be viewed as a safer option for patients initiating chronic dialysis, while benefiting from the robust efficacy in patients with or without inflammation with less IV iron use and lower transfusion rate compared to EPO in the dialysis patients.
We are privileged to have an opportunity to potentially introduce a new standard for anemia therapy for CKD patients with roxadustat, a first-in-class agent based on Nobel winning science. We believe these compelling efficacy results with demonstration of clinical benefits accompanied by the above safety results could serve as strong basis for marketing approval in both the U.S., Europe and other countries in the world. Working with our partner, AstraZeneca, we have made a substantial progress in preparing NDA for CKD anemia in patients on dialysis and in patients not on dialysis. We plan to submit the NDA for both indications before year-end.
We are working closely with Astellas, our European partner and expect to file the MAA for both indications in the first quarter of 2020.
Encouraged by the safety and efficacy results in CKD, we continue to expand treatment of anemia of other etiologies. In MDS, we have 2 ongoing clinical studies; a Phase III U.S. global study in transfusion-dependent MDS patients and a Phase II/III study in nontransfusion-dependent MDS patients in China. From Phase III global study results of the open-label lead-in portion, demonstrating roxadustat efficacy in MDS patients will be presented in an oral session of the upcoming American Society of Hematology Meeting in Orlando next month.
We have also started a Phase II U.S. study of roxadustat for treating chemotherapy-induced anemia which we believe to have much opportunity to address the unmet need of a large patient population.
Our founding CEO led pioneering HIF-PHI for anemia therapy.
We are committed to carry on Tom Neff's legacy to develop innovative medicines to improve patient care.
I now like to turn the call over to Chris Chung.