MACE/MACE+ endpoints evaluated across CKD patients not on dialysis and on dialysis Superiority in time to first MACE+ versus epoetin alfa in incident dialysis patients
SAN FRANCISCO, May 09, 2019 (GLOBE NEWSWIRE) -- FibroGen, Inc. (FGEN) today announced topline results from the pooled safety analyses of the global Phase 3 program for roxadustat, an inhibitor of hypoxia-inducible-factor (HIF) prolyl hydroxylase activity (HIF-PHI). The global pivotal Phase 3 trials were conducted by FibroGen and collaboration partners AstraZeneca and Astellas Pharma, Inc., for treatment of anemia in chronic kidney disease (CKD) patients across the non-dialysis-dependent (NDD), incident (newly initiated) dialysis, and dialysis-dependent (DD) CKD populations, enrolled from more than 50 countries.
These pooled analyses of adjudicated events for safety assessment of roxadustat are part of the overall benefit-risk assessment.
- For the planned new drug application (NDA) submission to the U.S. Food and Drug Administration (FDA), one of the key safety endpoints to be evaluated is Major Adverse Cardiac Events (MACE), a composite endpoint of all-cause mortality, stroke and myocardial infarction, in pooled analyses against placebo in NDD and against epoetin alfa in DD from the pivotal Phase 3 trials. Our NDA submission package to the FDA will be based on the totality of evidence, and we will continue to discuss the specific statistical standards with the FDA.
- For the European Medicines Agency (EMA), it was agreed that the primary safety assessment is MACE+, a composite endpoint of MACE plus heart failure requiring hospitalization and unstable angina requiring hospitalization.
“We are very pleased with what we believe are important positive results of MACE and MACE+ analyses in the dialysis-dependent, incident dialysis, and non-dialysis dependent CKD patients, supporting the safety of roxadustat in CKD patients,” said Thomas B. Neff, Chief Executive Officer, FibroGen. “Combined with the positive topline efficacy in hemoglobin (Hb) control in patients with or without concomitant inflammation, reduction of transfusion, and the encouraging results from the pooled analyses of Quality of Life and estimated glomerular filtration rate (eGFR) over time, these positive safety data give us confidence as we progress in preparation for the U.S. NDA and the Marketing Authorization Application (MAA) for EMA.”
Pooled MACE/MACE+ in DD-CKD Population
In the pooled analyses of around 4,000 dialysis patients, the upper bound of the 95% confidence interval (CI) was below the pre-specified non-inferiority margin for the time to first MACE+ analyses. Based on the MACE safety analyses of this population, we believe there is no clinically meaningful difference in risk of MACE between roxadustat and epoetin alfa.
Pooled MACE/MACE+ in Incident Dialysis CKD Subpopulation
The roxadustat global Phase 3 program enrolled over 1,500 incident dialysis patients, a subpopulation of DD-CKD population, which we believe offers a better setting for comparing roxadustat to epoetin alfa than the stable dialysis population, that is stable on both dialysis and erythropoiesis stimulating agent (ESA). Roxadustat demonstrated superiority to epoetin alfa in the time to first MACE+ in this subpopulation. In the MACE analysis, there is a trend toward reduced risk for patients on roxadustat, compared to epoetin alfa.
Pooled MACE/MACE+ in NDD-CKD Population
In the non-dialysis pool of approximately 4,300 patients, non-inferiority was demonstrated for roxadustat compared to placebo in the time to first MACE+, based on the upper bound of the 95% CI being below the prespecified non-inferiority margin. Based on the MACE safety analyses of this population, we believe there is no clinically meaningful difference in risk of MACE between roxadustat and placebo.
Of note, multiple MACE and MACE+ analyses in NDD-CKD from the roxadustat global Phase 3 program are being performed in intent-to-treat (ITT) analyses that demonstrated comparability of roxadustat to placebo. ITT is among the several statistical methods that we will discuss with the FDA. In these analyses, roxadustat was comparable based on a commonly applied non-inferiority margin of 1.3.
“Patients going through initiation of dialysis experience increased risks including mortality, and the NDD-CKD patients are often left untreated for anemia due to the safety concerns of the currently available therapies. We are particularly excited about the results indicating a reduction of risk of MACE+ events in incident dialysis patients, and the additional potential clinical benefits of roxadustat beyond anemia correction, to include attenuation of renal function decline and improvement of quality of life in NDD-CKD patients,” said K. Peony Yu, MD, Chief Medical Officer, FibroGen. “As we accumulate a body of evidence of roxadustat efficacy and safety with these adjudicated pooled analyses, we look forward to begin discussions with U.S. FDA on NDA submission.”
Further analyses of overall safety is ongoing and will inform on the overall benefit risk.
Slower eGFR Decline Observed in NDD patients
In the pooled analysis of eGFR change over time from the three NDD studies, we observed a slower eGFR decline in the roxadustat-treated patients versus placebo-treated patients in patients with baseline eGFR ≥ 15 mL/min/1.73 m2, with a treatment difference of 1.62 mL/min/1.73 m2 in eGFR change at 12 months from the baseline (p<0.0001), or a reduction by 38% in eGFR decline in the roxadustat arm relative to the placebo arm.
Improvements in Quality of Life Measures in NDD patients
In the pooled analysis from the three NDD studies, we observed statistically significant improvements from baseline to Week 12 in quality of life endpoints, including SF-36 Vitality subscale (p=0.0002), SF-36 Physical Functioning subscale (p=0.0369), FACT-AN Anemia subscale (p=0.0012), FACT-AN Total score (p=0.0056), and EQ-5D-SL VAS score (p=0.0005) when comparing roxadustat to placebo in CKD patients not on dialysis.
Efficacy Regardless of Inflammation Status
Roxadustat has demonstrated efficacy regardless of inflammation status as the mean achieved Hb levels and roxadustat dose requirements were not impacted by baseline c-reactive protein (CRP) levels in multiple Phase 3 studies, including in the U.S.-based SIERRAS study, which we believe is reflective of US dialysis practice under current ESA labeling restrictions. In SIERRAS, roxadustat dose requirements remained stable over time, while epoetin alfa dose requirements increased by 57% over 52 weeks in the epoetin alfa arm.
FibroGen and AstraZeneca will begin discussions with the U.S. FDA to prepare for regulatory submission, which is anticipated in September or October of 2019. We will also support Astellas’ submission of MAA to the EMA thereafter.
About Anemia Associated with CKD
Anemia can be a serious medical condition in which patients have insufficient red blood cells and low levels of Hb, a protein in red blood cells that carries oxygen to cells throughout the body. Anemia in CKD is associated with increased risk of hospitalization, cardiovascular complications and death, also frequently causing significant fatigue, cognitive dysfunction and reduced quality of life. Severe anemia is common in patients with CKD, cancer, myelodysplastic syndromes (MDS), inflammatory diseases, and other serious illnesses.
Anemia is particularly prevalent in patients with CKD. The prevalence of CKD in the adult population is estimated at 10-12% globally, and is generally a progressive disease characterized by gradual loss of kidney function that may eventually lead to kidney failure, or end stage renal disease, requiring dialysis or kidney transplant to survive. Blood transfusion is used for treating life-threatening severe anemia. However, blood transfusions reduce the patient’s opportunity for kidney transplant, increase risk of infections and the risk of complications such as heart failure and allergic reactions.
According to the United States Renal Data System (USRDS), over 14% of the U.S. adult population is affected by CKD, and a majority of dialysis-eligible CKD patients are currently on dialysis. It is estimated that approximately 507,000 patients are receiving dialysis in the U.S. as of 2016.
Roxadustat (FG-4592), discovered by FibroGen, is a first-in-class, orally administered small molecule currently approved in China for the treatment of anemia in CKD patients on dialysis. Roxadustat is a HIF-PHI that promotes erythropoiesis through increasing endogenous production of erythropoietin, improving iron regulation, and overcoming the negative impact of inflammation on hemoglobin syntheses and red blood cell production by downregulating hepcidin. Administration of roxadustat has been shown to induce coordinated erythropoiesis, increasing red blood cell count while maintaining plasma erythropoietin levels within or near normal physiologic range in multiple subpopulations of CKD patients, including in the presence of inflammation and without a need for supplemental intravenous iron.
FibroGen and collaboration partners are pursuing four approval pathways in major jurisdictions to prepare for commercialization worldwide:
- Astellas and FibroGen are collaborating on the development and commercialization of roxadustat for the treatment of anemia in territories including Japan, Europe, the Commonwealth of Independent States, the Middle East, and South Africa.
- AstraZeneca and FibroGen are collaborating on the development and commercialization of roxadustat for the treatment of anemia in the U.S., China, and other markets in the Americas and in Australia/New Zealand as well as Southeast Asia.
FibroGen and its partners have completed 35 Phase 1 and Phase 2 studies. The Phase 2 clinical studies have consistently demonstrated anemia correction and maintenance of hemoglobin levels in multiple subpopulations across a wide spectrum of CKD patients.
Globally, the Phase 3 program encompasses a total of 15 Phase 3 studies of roxadustat in both non-dialysis-dependent and dialysis-dependent CKD patients to support independent regulatory approvals in the U.S., Europe, Japan, and China. To date, positive topline results have been announced for 12 of the Phase 3 studies, with two supporting the China NDA for treatment of anemia in CKD patients on dialysis and not on dialysis, four supporting the Japan NDA for treatment of anemia in CKD patients on dialysis, and six supporting the U.S./EU submissions including today’s announcement of 3 studies by FibroGen. Roxadustat was approved by China National Medical Products Administration (NMPA) in December 2018, for treatment of anemia in CKD patients on dialysis. The Japan NDA submitted by Astellas is under review by the Japan Pharmaceuticals and Medical Devices Agency (PMDA).
Roxadustat is currently in Phase 3 clinical development for the treatment of anemia associated with MDS in the U.S. and in Phase 2/3 development for MDS in China.
FibroGen, Inc., headquartered in San Francisco, California, with subsidiary offices in Beijing and Shanghai, People’s Republic of China, is a leading biopharmaceutical company discovering and developing a pipeline of first-in-class therapeutics. The company applies its pioneering expertise in hypoxia-inducible factor (HIF), connective tissue growth factor (CTGF) biology, and clinical development to advance innovative medicines for the treatment of anemia, fibrotic disease, and cancer. Roxadustat, the company’s most advanced product candidate, is an oral small molecule inhibitor of HIF prolyl hydroxylase activity, completing worldwide Phase 3 clinical development for the treatment of anemia in chronic kidney disease (CKD), with a New Drug Application (NDA) now approved by the National Medical Products Administration (NMPA) in China. Our partner Astellas submitted a NDA for the treatment of anemia in CKD patients on dialysis in Japan in September 2018, which is currently under review by the Pharmaceuticals and Medical Devices Agency (PMDA). Roxadustat is in Phase 3 clinical development in the U.S. and Europe and in Phase 2/3 development in China for anemia associated with myelodysplastic syndromes (MDS). Pamrevlumab, an anti-CTGF human monoclonal antibody, is advancing towards Phase 3 clinical development for the treatment of idiopathic pulmonary fibrosis (IPF) and pancreatic cancer, and is currently in a Phase 2 trial for Duchenne muscular dystrophy (DMD). FibroGen is also developing a biosynthetic cornea in China. For more information, please visit www.fibrogen.com.
This release contains forward-looking statements regarding our strategy, future plans and prospects, including statements regarding the development of roxadustat, our interpretation of the pooled safety analyses and other analyses of the global Phase 3 program for roxadustat, the expected endpoints and potential standards for safety assessments of such data by the FDA and the EMA, the potential for and timing of an NDA submission to the FDA and an MAA submission to the EMA for potential marketing approval for roxadustat, the potential safety and efficacy profile of our product candidates, and our clinical, regulatory plans, and those of our partners. These forward-looking statements include, but are not limited to, statements about our plans, objectives, representations and contentions and are not historical facts and typically are identified by use of terms such as “may,” “will”, “should,” “on track,” “could,” “expect,” “plan,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue” and similar words, although some forward-looking statements are expressed differently. Our actual results may differ materially from those indicated in these forward-looking statements due to risks and uncertainties related to the continued progress and timing of our various programs, including the enrollment and results from ongoing and potential future clinical trials, and other matters that are described in our Annual Report on Form 10-K for the fiscal year ended December 31, 2018, and our Quarterly Report on Form 10-Q for the fiscal quarter ended March 31, 2019 filed with the Securities and Exchange Commission (SEC), including the risk factors set forth therein. Investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this release, and we undertake no obligation to update any forward-looking statement in this press release, except as required by law.
Karen L. Bergman
Vice President, Investor Relations and Corporate Communications
1 (415) 978-1433