What changed in this filing

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Item 1. Business

2021-03-01 compared with 2020-03-02 · 365 added, 488 removed, 864 unchanged (50% of the section changed)

We are a leading biopharmaceutical company discovering, developing and commercializing a pipeline of first-in-class therapeutics.

We apply our pioneering expertise in hypoxia-inducible factor (“HIF”) and connective tissue growth factor (“CTGF”) biology to advance innovative medicines for the treatment of anemia, fibrotic disease, and cancer.

Roxadustat, our most advanced product, is an inhibitor of HIF prolyl hydroxylase (“HIF-PH”) that acts by stimulating the body’s natural pathway of erythropoiesis, or red blood cell production.

In August 2019, roxadustat (China tradename:

爱瑞卓 ® ) received marketing authorization in the People’s Republic of China (“China”) for the treatment of anemia caused by chronic kidney disease (“CKD”) in non-dialysis-dependent patients.

Roxadustat was approved in China for the treatment of anemia caused by CKD in dialysis-dependent patients in December 2018.

In September 2019, roxadustat (Evrenzo ® ) was approved in Japan for the treatment of anemia associated with CKD in dialysis-dependent patients, and in January 2020, Astellas Pharma Inc.

(“Astellas”) submitted a supplemental New Drug Application (“NDA”) in Japan for the treatment of anemia in non-dialysis CKD patients.

In conjunction with our collaboration partners, AstraZeneca AB (“AstraZeneca”) and Astellas, we have completed the Phase 3 trials of roxadustat intended to support our NDA in the United States (“U.S.”) and Marketing Authorization Application (“MAA”) in the European Union and the United Kingdom (“Europe”) for the treatment of anemia in CKD .

Our NDA filing for roxadustat for the treatment of anemia in patients with dialysis-dependent CKD and in patients with non-dialysis-dependent CKD was accepted by the U.S.

Food and Drug Administration (“FDA”) in February, 2020.

Astellas is in the process of preparing an MAA for submission to the European Medicines Agency (“EMA”) in the second quarter of 2020 for the same indications.

In addition, AstraZeneca has submitted applications for marketing approval of roxadustat in CKD anemia in Canada, Mexico, Taiwan, Philippines, and Singapore.

We apply our pioneering expertise in hypoxia-inducible factor (“HIF”) biology, 2-oxoglutarate enzymology, and connective tissue growth factor (“CTGF”) biology to advance innovative medicines for the treatment of anemia, fibrotic disease, and cancer.

Roxadustat, our most advanced product, is an oral small molecule inhibitor of HIF-prolyl hydroxylase (“HIF-PH”) activity that acts by stimulating the body’s natural pathway of erythropoiesis, or red blood cell production.

We and our collaboration partner AstraZeneca AB (“AstraZeneca”) continue to expand the commercialization of roxadustat (tradename:

爱瑞卓 ® ) in the People’s Republic of China (“China”) where it is approved for the treatment of anemia caused by chronic kidney disease (“CKD”) in non-dialysis and dialysis patients.

Roxadustat was added to the National Reimbursement Drug List (“NRDL”), effective January 1, 2020.

As of the end of 2020, roxadustat was listed at hospitals that represent approximately 70% of the CKD anemia market opportunity in China and we continue to focus on adding additional temporary and permanent hospital listings for roxadustat.

In Japan, our partner Astellas Pharma Inc.

(“Astellas”) continues the commercial launch of EVRENZO® (roxadustat).

Astellas received approval of the supplemental New Drug Application (“NDA”) for the use of EVRENZO in patients with anemia of CKD not on dialysis from the Pharmaceuticals and Medical Devices Agency in November 2020, and it is now approved for the treatment of anemia associated with CKD in both non-dialysis and dialysis patients.

With respect to our United States (“U.S.”) NDA for roxadustat for the treatment of anemia due to CKD submitted for review in December 2019 to the U.S.

Food and Drug Administration (“FDA”), in December 2020, the FDA extended the review period of the NDA by three months for FibroGen to submit additional analyses of existing roxadustat clinical data, and set a new Prescription Drug User Fee Act (“PDUFA”) goal date of March 20, 2021.

On March 1, 2021, the FDA informed us that the Cardiovascular and Renal Drugs Advisory Committee will hold an advisory committee meeting to review the NDA for roxadustat.

The date of the advisory committee meeting has not been set.

As a result of this communication, we will not receive an approval decision by the PDUFA goal date.

In May 2020, the Marketing Authorization Application (“MAA”) for roxadustat for the treatment of anemia in patients with CKD, submitted by our partner Astellas, was accepted for regulatory review by the European Medicines Agency (“EMA”).

Astellas expects an approval decision mid-2021.

EVRENZO® (roxadustat) has also been approved for the treatment of anemia in CKD patients on dialysis and patients not on dialysis in Chile.

In collaboration with AstraZeneca, applications for marketing approval of roxadustat in CKD anemia have been submitted in Canada, Australia, Mexico, Brazil, Taiwan, South Korea, Philippines, Singapore, India, Colombia, and Thailand.

Beyond anemia in CKD, 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”).

We also began a Phase 2 clinical trial of roxadustat in the U.S.

in chemotherapy-induced anemia (“CIA”) in the third quarter of 2019.

Pamrevlumab is our human monoclonal antibody that inhibits the activity of CTGF, a central mediator and critical common element in the progression of fibrotic and fibro-proliferative diseases.

In 2019, we initiated a Phase 3 clinical program for the treatment of idiopathic pulmonary fibrosis (“IPF”) and a Phase 3 clinical program for locally advanced unresectable pancreatic cancer.

We also plan to initiate a Phase 3 program for the treatment of Duchenne muscular dystrophy (“DMD”) in 2020 .

We have completed enrollment in our Phase 2 clinical trial of roxadustat in the U.S.

in chemotherapy-induced anemia (“CIA”), and we expect topline data from this study in the second half of 2021.

Pamrevlumab is our first-in-class antibody developed to inhibit the activity of CTGF, a common factor in fibrotic and proliferative disorders characterized by persistent and excessive scarring that can lead to organ dysfunction and failure.

Pamrevlumab is in Phase 3 clinical development for the treatment of idiopathic pulmonary fibrosis (“IPF”), locally advanced unresectable pancreatic cancer (“LAPC”), and Duchenne muscular dystrophy (“DMD”).

ROXADUSTAT FOR THE TREATMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE

Roxadustat is an orally administered small molecule that treats anemia by a mechanism of action that is different from that of erythropoiesis stimulating agents (“ESAs”).

Roxadustat, as a HIF-PH inhibitor, relies on the natural mechanism by which the body responds to low oxygen levels.

HIF is a transcription factor comprised of a HIF-alpha and a HIF-beta subunit, both of which are required to stimulate erythropoiesis.

Under normal oxygen conditions, the HIF-alpha subunit is targeted for rapid degradation through the activity of a family of HIF-PH enzymes.

In collaboration with our partners AstraZeneca and Astellas, we have completed 16 Phase 3 studies worldwide in over 11,000 patients to support our regulatory filings in the U.S., Europe, China, and Japan.

After describing the mechanism of action of roxadustat, which is the first in a new class of potential anemia drugs, we provide some background on the CKD anemia market and a summary of our Phase 3 program along with some of the most important results.

Roxadustat Mechanism of Action

Roxadustat is an orally administered reversible inhibitor of HIF-PH.

Inhibition of prolyl hydroxylase stabilizes HIF, which stimulates a coordinated erythropoietic response that includes the increase of plasma endogenous erythropoietin (“EPO”) levels and reduction of hepcidin, a key regulator of iron homeostasis.

In healthy individuals under normal oxygen conditions, HIF-PH tags HIF-alpha for degradation and the HIF pathway is not activated.

However, under low oxygen conditions, the HIF-PH enzymes cannot function and HIF-alpha accumulates.

HIF-alpha then combines with HIF-beta, and the newly formed HIF complex initiates transcription of a number of genes involved in the erythropoietic process, which ultimately leads to increased oxygen delivery to tissues.

Roxadustat works by reversibly inhibiting the HIF-PH enzymes, thus mimicking this coordinated natural erythropoietic response through genes encoding the proteins involved in iron absorption, mobilization and transport as well as stimulation of red blood cell progenitors.

The coordinated erythropoiesis activated by roxadustat includes both the stimulation of erythroid maturation, by increasing the body’s production of erythropoietin (“EPO”), and an increase in iron availability for hemoglobin synthesis in part through a decrease in hepcidin levels, which is particularly important in patients with inflammation.

In anemia of CKD, roxadustat temporarily inhibits HIF-PH, preventing degradation of HIF-alpha and activating the HIF pathway, which stimulates a coordinated erythropoietic response that includes EPO production and the reduction of hepcidin.

The coordinated erythropoiesis activated by roxadustat includes both the stimulation of erythroid maturation, by increasing the body’s production of EPO, and an increase in iron availability for hemoglobin synthesis in part through a decrease in hepcidin levels, which is particularly important in patients with inflammation.

Patients taking roxadustat typically have a transient increase in circulating endogenous EPO levels at peak concentration within or near the physiologic range naturally experienced by humans adapting to hypoxic conditions such as at high altitude, following blood donation, or impaired lung function, such as pulmonary edema.

By contrast, ESAs act only to stimulate erythroid maturation without a corresponding increase in iron availability, and are typically dosed at well above the natural physiologic range of EPO.

By contrast, erythropoiesis stimulating agents (“ESAs”) act only to stimulate erythroid maturation without a corresponding increase in iron availability, and are typically dosed at well above the natural physiologic range of EPO.

The sudden demand for iron stimulated by ESA-induced erythropoiesis can lead to functional or absolute iron deficiency.

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Not only are IV iron and blood transfusions more costly than oral iron, but both are also associated with increased risk of hospitalization and death.

In contrast, the differentiated mechanism of action of roxadustat, which involves induction of the body’s own natural pathways to achieve a more complete erythropoiesis, has the potential to provide a safer and more effective treatment of anemia, including in the presence of inflammation, which normally limits iron availability.

The differentiated mechanism of action of roxadustat, which involves induction of the body’s own natural pathways to achieve a more complete erythropoiesis, has the potential to provide a safe and effective treatment for anemia, including in the presence of inflammation, which normally limits iron availability.

Background of Anemia in Chronic Kidney Disease

Chronic kidney disease is a progressive disease characterized by gradual loss of kidney function that may eventually lead to kidney failure or end-stage renal disease (“ESRD”) requiring dialysis or a kidney transplant to survive.

Chronic kidney disease is 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 a kidney transplant to survive.

CKD affects 12% to 14% of the global adult population.

CKD is more prevalent in developed countries but is also growing rapidly in emerging markets such as China.

Anemia can be a serious medical condition in which patients have insufficient red blood cells and low levels of hemoglobin, 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, and frequently causes significant fatigue, cognitive dysfunction, and considerable reduction of quality of life.

Anemia is a complication of chronic kidney disease and becomes increasingly common as the disease advances.

In the U.S., approximately 18 million adults have CKD Stages 3-5.

Based on literature and market research, we estimate 25%, 50%, and 55% of CKD non-dialysis patients in Stages 3, 4, and 5, respectively, have anemia.

This translates to an estimated 4.9 million CKD non-dialysis anemia patients, and we estimate that up to 50% may be addressable based on our expected label.

Additionally, 90% of CKD patients on dialysis in the U.S., or approximately 0.5 million, have anemia.

Anemia is a complication of CKD and can be a serious medical condition in which patients have insufficient red blood cells and low levels of hemoglobin, a protein in red blood cells that carries oxygen to cells throughout the body.

Anemia becomes increasingly common as kidney function declines and is associated with increased risk of hospitalization, cardiovascular complications and death, and frequently causes significant fatigue, cognitive dysfunction, and considerable reduction of quality of life.

There are approximately 39 million 1 CKD patients in the U.S., an estimated 6 million of whom have anemia 2 .

When ESAs were introduced in 1989, they dramatically reduced the need for blood transfusions in CKD patients, which was a material development since transfusions reduce the patient’s opportunity for a kidney transplant and increase the risk of infections and complications such as heart failure and allergic reactions.

However, multiple randomized clinical trials with ESAs suggested safety risks of ESA therapies, and as a result, the anemia guidelines and approved labels have changed to more restrictive use of ESAs.

In the U.S., while 93% of dialysis patients receive ESAs, in contrast, the percentage of patients who are on one or more ESAs at the time of dialysis initiation declined from 30% in 2006 to 13.6% in 2017, despite the well-recognized health risks of untreated anemia.

In addition to the safety concerns, which may be a greater impediment in the non-dialysis setting, other factors which contribute to the under-treatment of anemia in non-dialysis patients are related to the form of administration and accessibility of ESA products.

ESAs are administered by infusion or subcutaneous injections, which is more difficult outside of dialysis centers or nephrology practices where non-dialysis patients are typically treated.

Bikbov B et al.

“Global regional and national burden of chronic kidney disease 1990-2017 - a systematic analysis for the Global Burden of Disease Study 2017.” The Lancet, 395 (2020):

Based on 15.4% of CKD patients having anemia, (where anemia is defined as hemoglobin levels of ≤ 12 g/dL in women and ≤ 13 g/dL in men.

In the dialysis-dependent population, most patients start receiving ESAs when the patient is transitioning to dialysis care.

Patients face significant increased risk of death, cardiovascular events and hospitalizations during the first year on dialysis, and concurrently initiating anemia therapy adds complexity and safety risks.

In addition, patients at an advanced stage CKD are often affected by chronic inflammation that leads to functional iron deficiency, requiring IV iron, and reduced effectiveness of ESAs.

The Market Opportunity for Roxadustat

We believe there is a significant opportunity for roxadustat, a potentially safer and more effective anemia treatment, to address markets currently served by injectable ESAs.

According to IQVIA MIDAS™ reports, global ESA sales in all indications totaled $7.5 billion in 2018, driven primarily by $5.4 billion sold in the U.S.

and Europe, mostly for treatment of anemia in CKD.

We further believe that the number of patients requiring anemia therapy will grow steadily as the global CKD population and access to dialysis care continue to expand, particularly in China and other emerging markets including the rest of Asia, Latin America, Eastern Europe, the Middle East, and the Commonwealth of Independent States.

In addition, obesity, hypertension, and diabetes prevalence continue rising, and the mortality of ESRD patients is declining, particularly in many emerging markets.

Furthermore, we believe there is a significant opportunity for roxadustat to address patient segments that are currently not effectively served by ESAs, such as anemia in non-dialysis CKD due to under-diagnosis of CKD and under-treatment of anemia in this population.

Awareness of health consequences and the burden of CKD may also improve the diagnosis rate of CKD, and thus anemia of CKD.

Recently Completed Roxadustat Phase 3 Clinical Program in CKD Anemia

The table below summarizes the basis of our roxadustat U.S.

NDA and planned MAA filing in Europe.

Our NDA filing was accepted by the FDA in February 2020 for CKD anemia in both dialysis and non-dialysis patients.

The FDA has set a Prescription Drug User Fee Act goal date of December 20, 2020.

We expect Astellas to submit the MAA in Europe in the second quarter of 2020.

As of the end of 2018, there were over 550,000 CKD patients on dialysis in the U.S., a large majority of whom required anemia therapy.

There were approximately 127,000 incident dialysis patients in 2018.

Despite the higher risk of blood transfusions, cardiovascular events, and hospitalization in patients with anemia, only 14.6% of patients in 2018 were treated with ESAs prior to initiating dialysis notwithstanding a mean hemoglobin level of 9.3 g/dL at the time of dialysis initiation.

These treatment figures at the time of dialysis initiation demonstrate how undertreated CKD anemia is currently in non-dialysis patients.

However, we believe there will be approximately 2 million addressable non-dialysis CKD anemia patients in the U.S.

annually, based on the hemoglobin entry criteria in our Phase 3 clinical trials recommending initiation of treatment when a patient’s hemoglobin level is less than 10 g/dL.

In addition to the safety concerns raised for ESAs, which may have been a greater impediment to treatment in the non-dialysis setting, other factors which contribute to the recent historical under-treatment of anemia in non-dialysis patients are related to the form of administration and accessibility of ESA products.

ESAs are typically administered by subcutaneous injections, which is more difficult outside of dialysis centers or nephrology practices where non-dialysis patients are typically treated.

Roxadustat Phase 3 CKD Anemia Clinical Program

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Non-Inferior to Epoetin Alfa

Pooled Efficacy Results in Non-Dialysis Patients

Superior at Raising Hemoglobin

Roxadustat superiority in efficacy was demonstrated in pooled efficacy analyses across the three Phase 3 dialysis-dependent studies and the three non-dialysis-dependent studies.

In the non-dialysis pool (4,277 patients from OLYMPUS, ANDES, and ALPS), the mean change in hemoglobin (from baseline to the average between Weeks 28-52) in roxadustat patients was also significantly larger than in placebo patients (1.85 g/dL vs.

0.13 g/dL, p<0.001).

Efficacy at Raising Hemoglobin Irrespective of Iron Replete Status

In the non-dialysis pool, roxadustat increased hemoglobin (by 1.94 g/dL) regardless of whether patients were iron-replete (patients shown to have sufficient baseline stores of iron in their body, TSAT ≥20% and Ferritin ≥100 ng/mL) or not iron-replete.

Reduction In Risk of Rescue Therapy and Transfusion

The risk of rescue therapy (blood or red blood cell transfusion, ESA use, or IV iron) was significantly lower in the roxadustat arm (8.9%) than the placebo arm (31.1%) in the pooled non-dialysis patients with a hazard ratio (“HR”) = 0.19 (95% confidence interval “95% CI” of 0.16, 0.23), p<0.0001.

The percentage of patients receiving red blood cell transfusions during the first year of treatment was also significantly lower in the roxadustat arm (5.2%) as compared to the placebo arm (15.4%) (HR (95% CI) = 0.26 (0.21, 0.32), p<0.0001).

Reduction of Decline in Kidney Function as Measured by eGFR

In a post hoc subgroup analysis of 2,438 non-dialysis patients with baseline eGFR≥15, the one-year decline in estimated glomerular filtration rate (“eGFR,” a measure of the filtration function of kidney and renal disease progression) in roxadustat-treated patients (-2.8) was lower than that in placebo treated patients (-4.4), with a treatment difference of 1.6 mL/min/1.73m 2.

Reduction of LDL Cholesterol

In the pooled non-dialysis patients, roxadustat lowered low-density lipoproteins (“LDL”), with a mean change from baseline of -17.06 mg/dL compared to an increase of 1.30 mg/dL for placebo patients, a significant treatment difference of -19.83 mg/dL (p<0.0001).

Improvements in Quality of Life Measures

We have also observed improvements in quality of life.

In the pooled analysis from the three non-dialysis 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.

Pooled Efficacy Results in Dialysis Patients

Superior at Raising Hemoglobin

In the pooled dialysis studies (3,857 patients from HIMALAYAS, SIERRAS, and ROCKIES) the mean change in hemoglobin (from baseline to the average between Weeks 28-52) in roxadustat patients was significantly larger than in epoetin alfa patients (1.22 g/dL vs.

0.99 g/dL, p<0.001).

Efficacy at Raising Hemoglobin in Patients with Inflammation

In a subgroup of dialysis patients with inflammation (C-reactive protein (“CRP”) levels over 4.9 mg/L), the mean change in hemoglobin (from baseline to the average between Weeks 28-52) was significantly higher in roxadustat-treated patients (1.29 g/dL) than epoetin alfa treated patients (0.96 g/dL, p<0.0001).

Lower Intravenous (“IV”) Iron Requirements

In the dialysis pool, less mean monthly IV iron supplementation was required at Weeks 28-52 in patients receiving roxadustat versus patients receiving epoetin alfa in pooled analysis, p< 0.0001.

Reduction In Transfusion Risk

In the dialysis pool, during the first year of treatment, patients in the roxadustat arm had a lower transfusion risk (9.5%) as compared to the epoetin alfa arm (12.8%) (HR (95% CI) = 0.82 (0.679, 0.997), p=0.046).

Additional Highlights from Recent Publications and Presentations of Roxadustat in CKD Anemia

Pooled Cardiovascular Safety Results

In the U.S., the primary safety endpoint is time to first Major Adverse Cardiovascular Event (“MACE”), a composite endpoint of all-cause mortality, stroke and myocardial infarction.

In Europe, the primary safety endpoint is the time to first MACE+ (“MACE+”) which, in addition to the components in MACE, also includes hospitalization due to heart failure or unstable angina.

However, the FDA in the U.S., and the EMA in Europe, will each review MACE, MACE+, and all-cause mortality separately, in addition to other endpoints.

The below cardiovascular safety analyses reflect the pooling strategy and analytical approach we agreed on with the FDA.

Similar sets of analyses will be submitted to the EMA to serve as the basis for potential approval in dialysis and non-dialysis in Europe, and additional supportive analyses and sensitivity analyses as well as subgroup analyses were also included in the NDA and will be included in the MAA.

However, the FDA and EMA will each conduct their own benefit-risk analysis and may use additional statistical analyses other than those agreed with the FDA or set forth below.

In the U.S., the primary safety endpoint is time to first major adverse cardiovascular event (“MACE”), a composite endpoint of all-cause mortality, stroke and myocardial infarction, with secondary safety endpoint of “MACE+”, a composite endpoint consisting of the three components in MACE plus heart failure or unstable angina requiring hospitalization.The below cardiovascular safety analyses reflect the pooling strategy and analytical approach that was agreed upon with the FDA and presented in scientific journals/professional meetings.

Non-Dialysis - Pooled Cardiovascular Safety Data

In our pre-NDA meeting, the FDA agreed that the intent-to-treat analyses followed for long-term safety results would be our primary cardiovascular safety analysis method for non-dialysis in the U.S.

as it uses on-treatment and post treatment long term follow-up (until a common study end date) to account for the higher drop-out rate in the placebo arm.

The intent-to-treat analyses, inclusive of data during on-treatment and post treatment long term follow-up (until a common study end date), was used in our primary cardiovascular safety analysis method for non-dialysis in the U.S.

This approach accounts for the higher drop-out rate in the placebo arm.

The figure below shows that in the 4,270 pooled non-dialysis patients (OLYMPUS, ANDES, and ALPS), the risk of MACE, MACE+, and all-cause mortality in roxadustat patients were comparable to that in placebo patients based on a reference non-inferiority margin of 1.3.

Dialysis - Pooled Cardiovascular Safety Data

In the pooled on-treatment analysis of 3,880 dialysis patients (HIMALAYAS, SIERRAS, and ROCKIES), the risk of MACE and all-cause mortality in roxadustat patients were not increased (based on a reference non-inferiority margin of 1.3), and roxadustat lowered the risk of MACE+ by 14% compared to the active comparator epoetin alfa, based on a hazard ratio of 0.86 and an upper bound of 95% CI under 1.0.

In the pooled on-treatment analysis of 3,880 dialysis patients (HIMALAYAS, SIERRAS, and ROCKIES), the risk of MACE and all-cause mortality in roxadustat patients were comparable to epoetin alfa, based on a reference non-inferiority margin of 1.3.

Roxadustat lowered the risk of MACE+ by 14% compared to epoetin alfa based on a hazard ratio of 0.86 and an upper bound of 95% CI under 1.0.

The hazard ratios represent a point estimate of relative risk.

Incident Dialysis Subgroup - Pooled Cardiovascular Safety Data

In this program, incident dialysis patients are those who started participation in roxadustat Phase 3 studies within their first four months of dialysis initiation.

In this clinically important subgroup of 1,526 incident dialysis patients, roxadustat reduced the risk of MACE by 30% and MACE+ by 34%, with a trend towards lower all-cause mortality.

The lower MACE and MACE+ risks (compared to epoetin alfa) are based on hazard ratios of 0.70 and 0.66, respectively, with the upper bound of 95% CI under 1.0 in both.

We believe this incident dialysis subpopulation is the appropriate setting for comparison of roxadustat versus epoetin alfa since most incident dialysis patients were ESA-naïve or have had only limited exposure to ESAs prior to study entry.

In addition, the initiation of anemia therapy in this incident dialysis subgroup resembles clinical practice as the vast majority of US patients start anemia therapy early in dialysis treatment (during the first four months of treatment).

Non-Dialysis CKD Patients (ANDES) – FibroGen

ANDES is a 922-patient Phase 3, randomized, double-blinded, placebo-controlled trial designed to evaluate the efficacy and safety of roxadustat vs.

placebo for the treatment of anemia in patients with later stage CKD (Stages 3, 4 or 5) who are not dialysis-dependent.

primary efficacy endpoint:

roxadustat was superior to placebo in mean hemoglobin change from baseline to the average over Weeks 28 to 52 (2.00 vs.

0.16 g/dL, respectively, p<0.0001).

Europe primary efficacy endpoint:

a higher proportion of roxadustat-treated patients (86.0%) achieved a hemoglobin response (defined as achieving a hemoglobin level of at least 11 g/dL on two consecutive visits during the first 24-weeks of treatment and a hemoglobin increase of at least 1.0 g/dL in subjects with baseline hemoglobin >8.0 g/dL, or an increase of at least 2.0 g/dL in subjects with baseline hemoglobin ≤8.0 g/dL), as compared to placebo (6.6%), p<0.0001.

The proportion of subjects who received any rescue therapy (blood/red blood cell transfusion, ESA use, or IV iron) in the first 52 weeks of treatment was 8.9% in the roxadustat arm vs.

28.9% in the placebo arm (HR (95% CI) = 0.19 (0.138, 0.276), p<0.0001).

The proportion of subjects who received blood/red blood cell transfusion in the first 52 weeks of treatment was 5.6% in the roxadustat arm vs.

15.4% in the placebo arm (HR (95% CI) = 0.26 (0.165, 0.406), p<0.0001).

The mean change in LDL cholesterol from baseline to average over Weeks 12-28 was -18.48 mg/dL (n=564) in the roxadustat arm vs.

0.22 mg/dL (n=269) in the placebo arm, with a treatment difference of -17.26 mg/dL (p<0.0001).

In this study, roxadustat-treated patients had a sustained reduction in hepcidin whereas placebo patients did not have a reduction in hepcidin.

The mean change from baseline to Week 44 was -22.1μg/L in the roxadustat arm vs.

3.88 μg/L in the placebo arm, for a treatment difference between the two arms of -25.71 μg/L (95% CI:

-38.523, -12.903).

In this study, subjects in the roxadustat arm had a substantially higher overall study drug exposure compared to subjects in the placebo arm.

Study drug discontinuation was higher in the placebo arm compared to roxadustat arm, and the relative difference in discontinuation rates was especially pronounced in the lowest baseline eGFR category.

The overall exposure-adjusted safety profile of roxadustat observed during this study was comparable with placebo and consistent with that expected in the CKD study population.

The most commonly reported adverse events with roxadustat in this trial were nausea, hyperkalemia, constipation, and hypertension.

Non-Dialysis CKD Patients (ALPS) – Astellas

ALPS is Astellas’ Phase 3, randomized, double-blind, placebo-controlled study of the efficacy and safety of roxadustat for the treatment of anemia in CKD in 597 patients not on dialysis.

The trial met its primary endpoints by demonstrating superiority in efficacy vs.

placebo in terms of hemoglobin change from baseline at Weeks 28 to 52 (1.988 for roxadustat vs 0.406 for placebo, p<0.001).

Roxadustat was superior to placebo in its ability to lower LDL from baseline with an LS mean difference of -0.701 mmol/L (95% CI:

-0.83, -0.57).

Roxadustat was superior to placebo in delaying the need for rescue therapy (HR (95%CI) = 0.238 (0.17, 0.33), p<0.001).

The safety profile observed in this study was in line with the expected event profile in non-dialysis patients.

Common adverse events in both treatment groups were ESRD, hypertension, peripheral edema, and decreased glomerular filtration rate.

Non-Dialysis CKD Patients (OLYMPUS) – AstraZeneca

OLYMPUS is AstraZeneca’s Phase 3, randomized, double-blinded, placebo-controlled trial designed to evaluate the efficacy and safety of roxadustat vs.

placebo for the treatment of patients with anemia in CKD Stages 3, 4 or 5 whose disease progression is moderate to severe and who are non-dialysis-dependent.

The trial in 2,781 patients met its primary efficacy endpoint by demonstrating a statistically-significant improvement in mean change from baseline in hemoglobin levels averaged over Weeks 28 to 52 (1.75 g/dL) as compared with Placebo (0.40 g/dL).

Roxadustat also improved hemoglobin levels from baseline in a subgroup of patients with inflammation (CRP>5 mg/L), with a statistically significant mean increase of 1.75 g/dL, compared to 0.62g/dL with placebo.

Overall safety findings are generally consistent with the non-dialysis patient population.

For all patients, the most commonly reported adverse events in the intent-to-treat analysis set were ESRD, pneumonia, urinary tract infection and hypertension.

Stable Dialysis CKD Patients (PYRENEES) – Astellas

PYRENEES is Astellas’ Phase 3, randomized, active-controlled trial designed to assess the efficacy and safety of roxadustat vs.

epoetin alfa or darbepoetin alfa, for the treatment of anemia in 838 patients with CKD who are dialysis-dependent.

The trial met its primary efficacy endpoint:

roxadustat was considered non-inferior to ESAs based on the mean change from baseline in average hemoglobin levels at Weeks 28 to 52 (0.397 vs 0.183;

non-inferiority margin = -0.75).

Roxadustat was superior to ESAs in its ability to lower LDL from baseline with an LS mean difference of -0.377 mmol/L (95% CI:

-0.451, -0.304).

Roxadustat was superior to ESAs in reducing the need for monthly IV iron use (LS mean difference (95%CI) = -31.9 mg (-41.4, -22.4), p<0.001).

The safety profile observed in this study was in line with the expected event profile in dialysis patients.

There was a greater proportion of deaths in the roxadustat treatment group compared with the ESA group;

however, the study was not powered to assess risk of MACE events or death, as compared to the pooled analysis above.

Common adverse events in both treatment groups were hypertension, arteriovenous fistula thrombosis, headache, and diarrhea.

Stable and Incident Dialysis CKD Patients (ROCKIES) – AstraZeneca

ROCKIES is AstraZeneca’s Phase 3, randomized, open-label, active-controlled trial designed to assess the efficacy and safety of roxadustat vs.

epoetin alfa, for the treatment of anemia in patients with CKD who are dialysis-dependent.

The trial in 2,133 patients met its primary efficacy endpoint by demonstrating a statistically-significant improvement in mean change from baseline in hemoglobin levels averaged over Weeks 28 to 52 (0.77 g/dL) compared with epoetin alfa (0.68 g/dL).

Roxadustat also improved hemoglobin levels from baseline in a subgroup of patients with inflammation (CRP>5 mg/L, demonstrating a statistically significant improvement with a mean increase of 0.80 g/dL compared to 0.59 g/dL with epoetin alfa.

Patients treated with roxadustat used less monthly IV iron (mean = 59mg) compared to those treated with epoetin alfa (mean = 91mg) from Week 36 to the end of the study.

Adverse events with roxadustat were generally similar to those seen in patients treated with epoetin alfa and commonly found in dialysis patients.

In roxadustat-treated patients, the most commonly reported adverse events were diarrhea, hypertension, pneumonia, headache, and arteriovenous fistula thrombosis.

Stable and Incident Dialysis CKD Patients Study (SIERRAS) – FibroGen

SIERRAS is a 741-patient U.S.

Phase 3, randomized, open-label, active-controlled trial to assess the efficacy and safety of roxadustat compared to epoetin alfa for the treatment of anemia in dialysis CKD patients who were receiving stable doses of ESA prior to study participation.

primary efficacy endpoint:

the mean hemoglobin change from baseline to the average over Weeks 28 to 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.

Europe primary efficacy endpoint:

the mean hemoglobin change from baseline to the average over Weeks 28 to 36 was 0.54 g/dL (roxadustat) vs.

-0.03 g/dL (epoetin alfa), a least squares mean treatment difference of 0.55 g/dL with a 95% CI (0.40, 0.69).

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.

As seen in the figures below, in patients with inflammation (CRP>4.9 mg/L), roxadustat doses for maintaining hemoglobin levels were comparable to those with normal CRP and were stable over time as the effect on hemoglobin was durable, whereas epoetin alfa patients required higher mean doses in patients with inflammation (CRP>4.9 mg/L), doses which increased by approximately 50% from baseline after about one year.

In these patients with inflammation (CRP>4.9 mg/L) mean change in hemoglobin from baseline to Week 18-24 was 0.61 g/dL in roxadustat vs.

-0.03 g/dL in the epoetin alfa group, p<0.0001.

Subjects in the roxadustat group received lower mean IV iron during Weeks 28 to 52 than subjects in the epoetin alfa group (p=0.00091).

Roxadustat-treated patients had a greater reduction in hepcidin as compared to ESA-treated patients.

Additionally, a lower proportion of subjects on roxadustat received a red blood cell transfusion during treatment than the epoetin alfa group (12.5% and 21.1%, respectively, p=0.0337), with reduction in red blood cell transfusion risk by 33% compared with epoetin alfa;

HR (95% CI) = 0.67 (0.466, 0.970), p=0.0337.

Mean LDL cholesterol levels decreased in the roxadustat group from baseline to the average over Weeks 12 to 28 (-13.70 mg/dL) but increased in the epoetin alfa group (1.23 mg/dL) with a treatment difference of -14.67 mg/dL (p<0.0001).

The incidence of treatment emergent adverse events was comparable in the roxadustat and epoetin alfa arms and were generally consistent with those typically expected in study patient population of ESRD on chronic dialysis therapy.

The most commonly reported adverse events with roxadustat in this trial were nausea, hypertension, vomiting, and hyperkalemia.

Incident Dialysis CKD Patients Study (HIMALAYAS) – FibroGen

HIMALAYAS is a 1,043-patient Phase 3 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 ESRD and have had minimal or no exposure to an ESA prior to study participation.

primary efficacy endpoint:

the mean hemoglobin change from baseline to the average over Weeks 28 to 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% 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.

In subgroup analyses, roxadustat was also superior to epoetin alfa in hemoglobin change from baseline regardless of iron repletion and inflammation status.

Europe primary efficacy endpoint:

a higher proportion of roxadustat-treated patients (88.2%) achieved a hemoglobin response (defined as achieving a hemoglobin level of at least 11 g/dL on two consecutive visits during the first 24-weeks of treatment and a hemoglobin increase of at least 1.0 g/dL in subjects with baseline hemoglobin >8.0 g/dL, or an increase of at least 2.0 g/dL in subjects with baseline hemoglobin ≤8.0 g/dL), as compared to an 84.4% responder rate in the epoetin alfa arm, with the lower bound of the 95% CI (-0.7%, 7.7%) of the treatment difference in responder rate well above the non-inferiority margin of -15%.

Roxadustat-treated patients had a statistically significant reduction in hepcidin, a key regulator of iron metabolism, as compared to ESA-treated patients.

Roxadustat was shown to increase hemoglobin regardless of baseline inflammation status.

The most commonly reported adverse events with roxadustat in this trial were hypertension, diarrhea, and muscle spasms.

The safety profile of roxadustat in this study was consistent with results from prior roxadustat studies.

Data from the pooled incident dialysis patients were recently published in Kidney International Reports.

(Provenzano R et al.

Pooled Analysis of Roxadustat for Anemia in Patients with Kidney Failure Incident to Dialysis.

KI Reports 2021.

Available at https://www.kireports.org/article/S2468-0249(20)31851-9/fulltext.

Accessed on 11FEB2021.)

This is a clinically important subgroup of dialysis patients who started participation in roxadustat Phase 3 studies within their first four months of dialysis initiation.

In these 1,526 incident dialysis patients, roxadustat reduced the risk of MACE by 30% and MACE+ by 34%, with a trend towards lower all-cause mortality.

The lower MACE and MACE+ risks (compared to epoetin alfa) are based on hazard ratios of 0.70 and 0.66, respectively, with the upper bound of 95% CI under 1.0 for both endpoints.

We believe this incident dialysis subpopulation provides clinically and commercially relevant and generalizable results for comparison of roxadustat versus epoetin alfa because most incident dialysis patients (as opposed to stable dialysis patients) were ESA-naïve or had only limited exposure to ESAs prior to study entry.

In addition, the initiation of anemia therapy in this incident dialysis subgroup resembles clinical practice as the vast majority of U.S.

patients start anemia therapy early in dialysis treatment (during the first four months of treatment).

Iron-Metabolism Data

In non-dialysis patients, roxadustat was effective regardless of whether the “iron-repletion” criteria (ferritin >=100 ng/mL AND TSAT >=20%) were met, including the 40% of patients whose iron stores were below those required for ESA treatment.

Roxadustat also increased both serum iron and transferrin, resulting in the long-term clinical stability of TSAT while increasing the absolute amount of iron available for erythropoiesis.

In dialysis patients, roxadustat treated patients required less IV iron supplementation than patients treated with ESA.

Roxadustat facilitated iron transport and utilization by increasing both serum iron and iron-carrying capacity (TIBC), whereas these parameters were decreased and unchanged, respectively, with epoetin alfa.

We believe these changes were most likely driven by the downstream effects of reduced hepcidin in roxadustat treated patients.

Efficacy at Raising Hemoglobin Irrespective of Iron Replete Status

In the non-dialysis pool (4,277 patients from ANDES, OLYMPUS, and ALPS), roxadustat increased hemoglobin (by 1.94 g/dL) regardless of whether patients were iron-replete (patients shown to have sufficient baseline stores of iron in their body, TSAT ≥20% and Ferritin ≥100 ng/mL) or not iron-replete.

Sierras – U.S.

Only Dialysis Study

dialysis study SIERRAS, roxadustat raised and maintained Hb levels with stable mean doses over time regardless of baseline inflammation status, as measured by CRP levels.

The dose requirement of roxadustat was not impacted by inflammation.

Mean Hb and Mean Weekly Dose of roxadustat (Top Figure) and Epoetin Alfa (Bottom Figure) Over Time in Patients with hsCRP ≤ULN or >ULN (SIERRAS)

high-sensitivity C-reactive protein;

standard error;

upper limit of normal.

The proportion of patients who required at least one red blood cell transfusion in the first 52 weeks was 12.5% with roxadustat compared to 21.1% with epoetin alfa (p<0.05) in SIERRAS.

ROXADUSTAT FOR THE TREATMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE IN CHINA

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爱瑞卓 ® ) received marketing authorization in China for the treatment of anemia caused by CKD in non-dialysis-dependent patients.

Treatment for anemia caused by CKD in dialysis-dependent patients was approved in 2018.

Treatment for anemia caused by CKD in dialysis-dependent patients was approved in December 2018.

In July 2019, results from our two China Phase 3 clinical trials were published in the New England Journal of Medicine .

In December 2019, roxadustat was included on the updated National Reimbursement Drug List (“NRDL”) released by China’s National Healthcare Security Administration.

In December 2019, roxadustat was included on the updated NRDL released by China’s National Healthcare Security Administration.

Roxadustat is included on the NRDL for the treatment of anemia in CKD.

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With the substantial growth rate of dialysis patients (over 10% per year from 2011 to 2017), the Ministry of Health and the Chinese Society of Nephrology have publicly recognized the need for further investment in dialysis infrastructure.

The prevalence rate of CKD dialysis patients that have anemia (defined as hemoglobin < 10g/dL) is estimated to be over 90%.

The prevalence of CKD dialysis patients that have anemia (defined as hemoglobin < 10g/dL) is estimated to be over 90%.

Dialysis treatment is delivered in the form of hemodialysis or peritoneal dialysis.

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With recent regulatory changes, the number of privately owned dialysis clinics is growing at a rapid pace, a trend that has provided additional capacity to meet the growing demand.

The remaining 14-15% of CKD patients (approximately 100,000) are on peritoneal dialysis, which is self-administered at home by patients, a setting roxadustat , with its oral administration, is particularly well-suited for roxadustat .

The remaining 14-15% of CKD patients (approximately 100,000) are on peritoneal dialysis, which is self-administered at home by patients, a setting which roxadustat is particularly well-suited for due to its oral administration.

Peritoneal dialysis patients typically visit their nephrologists on a monthly basis at the hospital for monitoring and follow-up.

“Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis” N Engl J Med 381 (2019):

10.1056/NEJMoa1901713

“Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis” N Engl J Med 381 (2019):

10.1056/NEJMoa1813599

Non-Dialysis-Dependent CKD

We estimate that there are over 10 million Stage 3-5 non-dialysis CKD patients in China with anemia (defined as hemoglobin < 10g/dL).

We believe the addressable population of non-dialysis patients with anemia (anemic patients that have been diagnosed and treated for CKD) is approximately 2-3 million, with 1-2 million in Stages 3 and 4 and 1 million in Stage 5 non-dialysis.

We believe the addressable population of non-dialysis patients with anemia (anemic patients that have been diagnosed and treated for CKD) is approximately 2-3 million, with 1-2 million of these addressable patients in Stages 3 and 4 and 1 million in Stage 5 non-dialysis.

This Stage 5 population that is dialysis-eligible but not receiving dialysis is characteristic of developing markets like China, and presents a particular opportunity for roxadustat, as many patients have severe anemia.

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AstraZeneca is our commercialization partner for roxadustat in China.

Under our collaboration agreement, AstraZeneca will lead commercialization activities and has responsibility for sales and marketing, and market access.

FibroGen has responsibility for medical affairs, manufacturing (as the Marketing Authorization Holder), executing sales to distributors, and pharmacovigilance.

FibroGen and AstraZeneca will work together to manage distribution.

Under our collaboration agreement, AstraZeneca leads commercialization activities and has responsibility for sales and marketing, and market access.

FibroGen has responsibility for medical affairs, manufacturing (as the Marketing Authorization Holder), and pharmacovigilance.

Pricing and Reimbursement

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The list is effective for a standard two-year period from January 1, 2020 to December 31, 2021.

The negotiated price for a roxadustat 50 mg capsule is RMB 95.

Roxadustat will be subject to price re-negotiation at the end of 2021.

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We expect roxadustat reimbursement rates will be largely consistent with those ESAs listed on the NRDL.

We believe in the next few years and in many parts of the country, dialysis patients will generally be reimbursed for 80-90% of their costs for roxadustat and non-dialysis patients in the 50-70% range.

We believe in the next few years and in many parts of the country, reimbursement will reach a level where patient out-of-pocket costs will be in the range of 10-20% for dialysis and 30-50% for non-dialysis.

Hospital Listing

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ROXADUSTAT FOR THE TREATMENT OF ANEMIA IN CHRONIC KIDNEY DISEASE IN JAPAN

In September 2019, roxadustat (Evrenzo ® ) was approved in Japan for the treatment of anemia associated with CKD in dialysis patients.

Our collaboration partner Astellas launched Evrenzo in November 2019, targeting healthcare providers that care for approximately 330,000 dialysis patients across Japan.

In January 2020, Astellas submitted a supplemental NDA in Japan for the treatment of anemia in non-dialysis CKD patients, supported by three clinical studies in more than 500 Japanese non-dialysis patients with anemia associated with CKD.

In Japan, our partner Astellas continues the commercial launch of EVRENZO® (roxadustat), targeting healthcare providers that care for approximately 330,000 dialysis patients across Japan.

EVRENZO is now approved for the treatment of anemia associated with CKD in both non-dialysis and dialysis patients.

The supplemental NDA for the use of roxadustat in patients with anemia of CKD not on dialysis was approved in November 2020 by the Pharmaceuticals and Medical Devices Agency.

In addition, the 14-day Prescription Rule that is typically in place for the first 12 months of a product’s availability in Japan was lifted in December of 2020, creating a potential catalyst for EVRENZO utilization given it is the first HIF-PH inhibitor to no longer have this limitation.

ROXADUSTAT FOR THE TREATMENT OF CHEMOTHERAPY-INDUCED ANEMIA AND ANEMIA ASSOCIATED WITH MYELODYSPLASTIC SYNDROMES

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and 3.2 million in China.

Eighty percent of those patients in developed countries and 40% of patients in China develop CIA.

Between 60% and 80% of these patients develop anemia.

The incidence and severity of CIA depend on a variety of factors, including the tumor type or the level of toxicity of the therapy, and further increases with each successive chemotherapy round.

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However, not all CIA patients respond to ESA therapy, which may be due to the etiology of their CIA or inflammatory comorbidity.

ESA use also has associated toxicities, including increased thrombotic events, possible decreased survival and accelerated tumor progression, as published from randomized clinical trials and meta-analyses, that led to label restrictions and box warnings for ESAs in cancer populations in 2007, followed by the ESA Risk Evaluation and Mitigation Strategy (“REMS”) program.

ESA use also has associated toxicities, including increased thrombotic events, possible decreased survival and accelerated tumor progression, as published from randomized clinical trials and meta-analyses, that led to label restrictions and boxed warnings for ESAs in cancer populations in 2007, followed by the ESA Risk Evaluation and Mitigation Strategy (“REMS”) program.

Market Opportunity for Roxadustat in Chemotherapy-Induced Anemia

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since the reported safety risks of ESA use in cancer patients in 2006, from estimated $2.5 billion in 2006 to less than $0.5 billion in 2019.

During the same period, the prevalence of diagnosed CIA remained at similar levels, and is expected to grow slightly as a marginal decline of chemotherapy use is offset by an aging population.

We believe that if our clinical program shows an acceptable safety and efficacy profile, roxadustat would have the potential to address anemia in this population of patients undergoing chemotherapy, including, potentially, those patients with concomitant inflammation.

During the same period, the prevalence of diagnosed CIA remained at similar levels, and is expected to grow slightly.

We believe that if our clinical program shows an acceptable safety and efficacy profile, roxadustat would have the potential to address anemia in this population of patients undergoing chemotherapy.

Clinical Development of Roxadustat in Chemotherapy-Induced Anemia

We began a Phase 2 proof of concept clinical trial of roxadustat in the U.S.

in CIA in the third quarter of 2019.

This is a single-arm open label study investigating the efficacy and safety of roxadustat for the treatment of anemia in patients receiving myelosuppressive chemotherapy treatment for non-myeloid malignancies, with treatment duration of 16 weeks, and will enroll up to 100 patients.

We have completed enrollment in WHITNEY, our Phase 2 clinical trial of roxadustat in the U.S.

This is a single-arm open label study investigating the efficacy and safety of roxadustat for the treatment of anemia in 92 patients receiving myelosuppressive chemotherapy treatment for non-myeloid malignancies, with a treatment duration of 16 weeks.

We expect topline data from this study in the second half of 2021.

Background of Anemia in Myelodysplastic Syndromes

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In most MDS patients, the cause of the disease is unknown.

Incidence and prevalence of MDS are not yet well understood, and may be greatly underestimated.

MDS diagnosis became reportable under the World Health Organization oncology classification system only in 2001, and since then cases of MDS have been tracked by cancer registries.

The prevalence of MDS in the U.S.

is estimated to be between 60,000 and 170,000, and continues to rise as more therapies become available and patients are living longer with MDS.

We estimate that currently, approximately 70,000 patients are diagnosed with MDS in the United States.

Annual incidence rates are estimated to be 4.9/100,000 adults in the U.S., and 1.51/100,000 adults in China.

Anemia is the most common clinical presentation in MDS, seen in approximately 80% of MDS patients, and producing symptoms, including fatigue, weakness, exercise intolerance, shortness of breath, dizziness, and cognitive impairment.

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New strategies to broaden the eligible population, improve anemia and maintain adequate iron balance, as well as avoidance of transfusions, are highly desired in managing patients with MDS.

Reblozyl® (luspatercept) was approved by the FDA in April 2020 for the treatment of anemia in adults with MDS with ring sideroblasts or myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis who need regular red blood cell transfusions and have not responded well to or cannot receive an ESA.

It is the first and only erythroid maturation agent approved in the U.S., Europe, and Canada and is part of a global collaboration between Acceleron Pharma, Inc.

and Bristol Myers Squibb.

In 2020, Reblozyl net revenue was $274 million, including $115 million in Q4 2020.

Market Opportunity for Roxadustat in Myelodysplastic Syndromes

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Moreover, in anemia of CKD, roxadustat has demonstrated the ability in clinical trials to increase and maintain hemoglobin levels in the presence of inflammation as measured by CRP, where ESAs have shown limited effect.

We believe that we may be able to replicate this result in MDS anemia patients, where it is not uncommon for patients to present with autoimmune and inflammatory conditions.

We believe that roxadustat has the potential to replicate this result in MDS anemia patients, where it is not uncommon for patients to present with autoimmune and inflammatory conditions.

Clinical Development of Roxadustat in Myelodysplastic Syndromes

We are conducting a Phase 3 placebo controlled, double-blind clinical trial to evaluate the safety and efficacy of roxadustat for treatment of anemia in MDS in the U.S.

We continue to enroll this 160-patient randomized, double-blind, placebo-controlled Phase 3 clinical study of roxadustat in transfusion-dependent, lower-risk MDS patients, in which subjects are randomized 3:2 to receive roxadustat or placebo three-times-weekly.

We are continuing to enroll MATTERHORN, our Phase 3 placebo controlled, double-blind clinical trial to evaluate the safety and efficacy of roxadustat for treatment of anemia in MDS in the U.S.

This 160-patient trial is studying roxadustat in transfusion-dependent, lower-risk MDS patients, in which subjects are randomized 3:2 to receive roxadustat or placebo three-times-weekly.

The primary endpoint is the proportion of patients who achieve transfusion independence by 28 weeks with secondary endpoints and safety evaluated at 52 weeks.

We expect topline data from this study in the first half of 2022.

In the open-label dose-finding component of this study, 24 lower-risk, transfusion dependent MDS patients with anemia were enrolled in three sequential starting dose cohorts (1.5 mg/kg, 2.0 mg/kg, and 2.5 mg/kg), with roxadustat doses adjusted every eight weeks per a pre-defined algorithm based on hemoglobin response.

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The dose level of 2.5 mg/kg was selected as the starting dose for the double-blind component of the study.

In China, we continue to enroll the open-label portion of our Phase 2/3 clinical trial to evaluate the safety and efficacy of roxadustat in non-transfusion dependent, lower-risk MDS patients with anemia.

After the open-label portion we expect to begin the 135-patient double-blind, placebo-controlled Phase 3 portion of the study, in which subjects will be randomized 2:1 to receive roxadustat or placebo three-times weekly for 26 weeks.

In China, we are preparing to enroll the Phase 3 double-blind, placebo-controlled portion of our Phase 2/3 clinical trial to evaluate the safety and efficacy of roxadustat in non-transfusion dependent, lower-risk MDS patients with anemia.

One hundred thirty-five subjects will be randomized 2:1 to receive roxadustat or placebo three-times weekly for 26 weeks.

The primary endpoint for this study is percentage of patients achieving a hemoglobin response.

Research at FibroGen

The HIF-PH enzymes that are the targets of roxadustat belong to a broader family of enzymes known as 2-oxoglutarate (2OG)-dependent oxygenases.

In humans, this family comprises more than 60 members that play important roles in a diverse range of biological processes including collagen biosynthesis, oxygen sensing, epigenetic regulation, nucleic acid modification/repair, and lipid metabolism.

The first members of this enzyme family to be characterized were the collagen prolyl hydroxylases, which play a critical role in the biosynthesis of collagen and as a result, are potential targets for the treatment of fibrotic disease.

The HIF-PH enzymes regulate the stability of the HIF transcription factor, which not only has therapeutic relevance for the treatment of anemia as exemplified by roxadustat, but also has implications for other diseases where activation of the HIF pathway would be expected to have beneficial effects.

Other members of the 2OG-dependent oxygenase family with relevance to human disease include the Jumonji domain-containing histone demethylases, which are emerging cancer targets.

The fact that all members of the 2OG-dependent oxygenase enzyme family use 2OG as a co-substrate makes them viable targets for small molecule inhibitors that compete with 2OG.

FibroGen has been a world leader in inhibition of enzymes belonging to this family, and.

our internal medicinal chemistry efforts have generated a large library of novel compounds designed to target the 2OG-dependent oxygenase family.

PAMREVLUMAB FOR THE TREATMENT OF FIBROSIS AND CANCER

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Our data to date indicate that pamrevlumab is a promising and highly differentiated product candidate with broad potential to treat a number of fibrotic diseases and cancers.

We are currently conducting Phase 3 studies in pancreatic cancer and IPF and a Phase 2 trial in DMD.

In the U.S., the FDA has granted Orphan Drug Designation to pamrevlumab for the treatment of IPF, locally advanced unresectable pancreatic cancer, and DMD.

We are currently conducting Phase 3 studies in pancreatic cancer, IPF and DMD.

In the U.S., the FDA has granted Orphan Drug Designation to pamrevlumab for the treatment of IPF, LAPC, and DMD.

In addition, the EMA has granted Orphan Medicinal Product Designation to pamrevlumab for the treatment of DMD.

Pamrevlumab has also received Fast Track designation from the FDA for the treatment of both IPF and locally advanced unresectable pancreatic cancer.

Pamrevlumab has also received Fast Track designation from the FDA for the treatment of both IPF and LAPC.

Overview of Fibrosis

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There are currently two therapies approved to treat IPF in Europe and the U.S., pirfenidone and nintedanib.

The approvals and subsequent launches of pirfenidone and nintedanib have clearly shown the commercial potential in IPF.

The approvals and subsequent launches of Esbriet (pirfenidone) and Ofev (nintedanib) have clearly shown the commercial potential in IPF.

Hoffmann-La Roche (“Roche”) reported worldwide sales of approximately $1.1 billion for 2019 and $1.2 billion for 2020 for Esbriet® (pirfenidone).

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Phase 3 Clinical Development – Randomized, Double-Blind, Placebo-Controlled Trials of Pamrevlumab in IPF

We continue to enroll ZEPHYRUS, our double-blind, placebo-controlled Phase 3 trial of pamrevlumab in IPF patients.

In 2020, we will initiate a second IPF study similar in design to ZEPHYRUS.

Each study will target approximately 340 patients.

The primary U.S.

efficacy endpoint for each study is change from baseline in forced vital capacity (“FVC”).

The primary efficacy endpoint in Europe for each study is disease progression (defined by a decline in FVC percent predicted of greater than or equal to 10% or death).

We are conducting ZEPHYRUS-1, our Phase 3 trial of pamrevlumab in IPF patients, as well as our newly initiated ZEPHYRUS-2, a second IPF Phase 3 study.

Both studies are double-blind, placebo-controlled Phase 3 trials targeting approximately 340 patients, each with a primary U.S.

efficacy endpoint of change from baseline in forced vital capacity.

The primary efficacy endpoint in Europe for each study is disease progression (defined by a decline in forced vital capacity (“FVC”) percent predicted of greater than or equal to 10% or death).

Secondary endpoints will include clinical outcomes of disease progression, patient reported outcomes, and quantitative changes in lung fibrosis volume from baseline.

The COVID-19 pandemic has affected enrollment in these IPF trials, more so than our other studies due to the vulnerability of this patient population.

In addition to efforts we are making in ensuring patient safety, we are also working to expand enrollment through a number of methods, including expanding the number of clinical sites in China.

PRAISE – Study 067 – Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of Pamrevlumab in IPF

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Lung function assessments were conducted at baseline and at Weeks 12, 24, 36 and 48.

Quantitative HRCT assessments were performed at baseline and on Weeks 24 and 48.

Quantitative HRCT assessments were performed at baseline and at Weeks 24 and 48.

Pamrevlumab met the primary efficacy endpoint of change of FVC percent predicted, a measure of a patient’s lung volume as a percentage of what would be expected for such patient’s age, race, sex and height.

The average decline (least squares mean) in FVC percent predicted from baseline to Week 48 was 2.85 in the pamrevlumab arm (n=50) as compared to an average decline of 7.17 in the placebo arm (n=51), a statistically significant difference of 4.33 (p=0.0331, using a linear slope analysis in intent-to-treat population).

The average decline (least squares mean) in FVC percent predicted from baseline to Week 48 was 2.9 in the pamrevlumab arm (n=50) as compared to an average decline of 7.2 in the placebo arm (n=51), a statistically significant difference of 4.33 (p=0.033).

FVC Change by Visit

Pamrevlumab-treated patients had an average decrease (least squares mean) in FVC of 129 ml at Week 48 compared to an average decrease of 308 ml in patients receiving placebo, a statistically significant difference of 178 ml (p=0.0249, using a linear slope analysis in the intent-to-treat population).

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In addition, the pamrevlumab-treated arm had a lower proportion of patients (10%) who experienced disease progression (defined by a decline in FVC percent predicted of greater than or equal to 10% or death), than did the placebo arm (31.4%) at Week 48 (p=0.0103).

The percentage of pamrevlumab patients who experienced disease progression and discontinued therapy was less than 15% of that in the placebo arm.

In this study, we measured change in quantitative lung fibrosis from baseline to Week 24 and Week 48 using quantitative HRCT.

The pamrevlumab arm achieved a statistically significant reduction in the rate of progression of lung fibrosis compared to placebo using HRCT to measure quantitative lung fibrosis (“QLF”).

Proportion of Patients with Decline in Percentage of Predicted FVC of 10% or Greater, or Death, by Visit

In this study, we measured change in quantitative lung fibrosis (“QLF”) from baseline to Week 24 and Week 48 using quantitative HRCT.

The pamrevlumab arm achieved a statistically significant reduction in the rate of progression of lung fibrosis compared to placebo using HRCT to measure QLF.

The change in QLF volume from baseline to Week 24 for pamrevlumab-treated patients was 24.8 ml vs.

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151.5 ml in patients on placebo, with a treatment difference of -76.2 ml, p=0.038.

As in our previous open label Phase 2 study, a correlation between FVC percent predicted and quantitative lung fibrosis was confirmed at both Week 24 and 48 in this study.

Change from Baseline in Volume of Quantitative Lung Fibrosis (mL) in the Intention-to-Treat Population

As in our previous open label Phase 2 study, a correlation between FVC percent predicted and QLF was confirmed at both Week 24 and 48 in this study.

We are not aware of any other IPF therapies that have shown a statistically significant effect on lung fibrosis as measured by quantitative HRCT analysis.

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The SGRQ quality of life measurement has been validated in chronic obstructive pulmonary disease.

In the patients that were evaluated by the UCSD Shortness of Breath Questionnaire, pamrevlumab-treated patients had a significant attenuation of their worsening dyspnea in comparison to placebo.

In the patients that were evaluated by the UCSD Shortness of Breath Questionnaire, pamrevlumab-treated patients had a significant attenuation of their worsening dyspnea in comparison to placebo patients.

Pamrevlumab was well-tolerated in the placebo-controlled study.

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Study 049 – Open-Label Phase 2 Trial of Pamrevlumab in IPF

We completed an open-label extension of Study 049, a Phase 2 open-label, dose-escalation study to evaluate the safety, tolerability, and efficacy of pamrevlumab in 89 patients with IPF.

During the initial one-year treatment period, pamrevlumab was administered at a dose of 15 mg/kg in Cohort 1 (53 patients) and 30 mg/kg in Cohort 2 (36 patients) by IV infusion every three weeks for 45 weeks.

After 45 weeks of dosing, subjects whose FVC declined less than predicted were allowed to continue dosing in an extension study until they had disease progression.

Nineteen patients from Cohort 1 (35.8%) and 18 patients from Cohort 2 (50.0%) entered the extension study.

Efficacy endpoints were pulmonary function assessments, extent of pulmonary fibrosis as measured by quantitative imaging and measures of health-related quality of life.

Our completed open-label extension of Study 049, a Phase 2 open-label, dose-escalation study to evaluate the safety, tolerability, and efficacy of pamrevlumab in 89 patients with IPF, was consistent with our results from our randomized, double-blind, placebo-controlled Phase 2 clinical trial PRAISE.

We presented data from our open-label Phase 2 IPF extension study (049) at the International Colloquium on Lung and Airway Fibrosis in November 2016, reporting that no safety issues were observed during prolonged treatment with pamrevlumab.

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Trends regarding improved or stable pulmonary function and stable fibrosis observed during the initial one-year study were also observed in the extension study.

In Cohort 1, we enrolled patients with a wide range of disease severity to assess safety and efficacy.

Baseline FVC percent predicted for Cohort 1 was 43% to 90%, with a mean of 62.8%.

In contrast, other IPF clinical trials, such as those for pirfenidone and nintedanib, have enrolled patients who on average had mild to moderate disease (mean FVC percent predicted 73.1% to 85.5%).

Fourteen patients in Cohort 1 withdrew, and ten of the 14 had severe disease.

In order to enroll IPF patients similar to those in other IPF trials, we amended the protocol for Cohort 2 to include only patients with mild to moderate disease (FVC ≥ 55% predicted).

Baseline FVC percent predicted for Cohort 2 was 53% to 112%, with a mean of 72.7%.

Based on this definition of disease severity, 37 patients in Cohort 1 and 32 patients in Cohort 2 had mild to moderate disease.

The table below provides a summary of the observed quantitative change in fibrosis for mild to moderate patients in Cohorts 1 and 2 as measured by quantitative HRCT.

Twenty-four percent of these patients had improved fibrosis at Week 48.

We believe that this is the first trial to demonstrate a reversal of fibrosis (as measured by HRCT) in a subset of IPF patients.

Stable fibrosis has been considered the only achievable favorable outcome in IPF.

The table below sets forth the number of patients who showed stable or improved fibrosis at Weeks 24 and 48 compared to the amount of fibrosis at the start of the trial.

Changes in Fibrosis in Patients with Mild to Moderate IPF Treated with Pamrevlumab in FGCL-3019-049

Stable or Improved

Compared to Baseline

Improved Compared to

Improved Compared

Eighty-nine patients had at least one adverse event.

The most common reported events were cough, fatigue, shortness of breath, upper respiratory tract infection, sore throat, bronchitis, nausea, dizziness, and urinary tract infection.

Including the open-label extension, there were 45 serious adverse events in 31 patients, four of which were considered possibly related by the principal investigator to the investigational drug.

After investigation, it is our belief that there is no causal relationship between pamrevlumab and the serious adverse events deemed possibly related by the principal investigator.

During the first year of treatment there were 38 treatment-emergent serious adverse events in 24 patients.

Adverse events observed to date are consistent with typical conditions observed in this patient population.

Pancreatic Cancer

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Pancreatic ductal adenocarcinoma, or pancreatic cancer, is the third leading cause of cancer deaths in the U.S.

According to the European Commission’s European Cancer Information System, there were 100,005 new cases of pancreatic cancer and 95,373 deaths from pancreatic cancer in the Europe projected for 2018.

According to the European Commission’s European Cancer Information System, there were 100,005 new cases of pancreatic cancer and 95,373 deaths from pancreatic cancer in Europe projected for 2018.

The National Cancer Center of Japan estimated that there were 36,239 new cases of pancreatic cancer in 2014, increased from 24,442 cases in 2004.

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Phase 3 Clinical Development – Randomized, Double-Blind, Placebo-Controlled Trial of Pamrevlumab in Locally Advanced, Unresectable Pancreatic Cancer

We continue to enroll LAPIS, our double-blind placebo controlled Phase 3 trial of pamrevlumab as a neoadjuvant therapy for locally advanced unresectable pancreatic cancer.

We intend to enroll approximately 260 patients, randomized 1:1 to receive either pamrevlumab, in combination with gemcitabine and nab-paclitaxel, or placebo with gemcitabine and nab-paclitaxel.

After completion of the 6-month treatment period, if the results show an improved resection rate in the pamrevlumab arm, we may request a meeting with the FDA to discuss the adequacy of these results to support a marketing application under the provisions of accelerated approval.

After this interim assessment of resection rates, the study will continue to collect data on overall survival, the primary endpoint.

We continue to enroll LAPIS, our double-blind placebo controlled Phase 3 clinical program for pamrevlumab as a neoadjuvant therapy for LAPC.

We intend to enroll approximately 260 patients, randomized at a 1:1 ratio to receive either pamrevlumab or placebo, in each case in combination with gemcitabine and nab-paclitaxel.

We expect topline resection data from this study in the second half of 2022.

Study 069 – Randomized, Open-Label, Active-Controlled Phase 1/2 Trial of Pamrevlumab in Locally Advanced Pancreatic Cancer

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Furthermore, a higher proportion of pamrevlumab-treated patients (33.3%) achieved surgical resection than those who received chemotherapy alone (7.7%).

In addition, this data showed improved overall survival among patients who were resected vs.

In addition, this data showed improved overall survival among patients whose tumors were resected vs.

not resected (NE vs.

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No increase in serious adverse events was observed in the pamrevlumab arm and no delay in wound healing was observed post-surgery.

Patients with locally advanced unresectable pancreatic cancer have median survival of less than 12 months, only slightly better than patients with metastatic pancreatic cancer, whereas patients with resectable pancreatic cancer have a much better prognosis with median survival of approximately 23 months and some patients being cured.

Patients with LAPC have median survival of less than 12 months, only slightly better than patients with metastatic pancreatic cancer, whereas patients with resectable pancreatic cancer have a much better prognosis with median survival of approximately 23 months and some patients being cured.

If pamrevlumab in combination with chemotherapy continues to demonstrate an enhanced rate of conversion from unresectable cancer to resectable cancer, it may support the possibility that pamrevlumab could provide a substantial survival benefit for locally advanced pancreatic cancer patients.

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Numerous pre-clinical studies including those in the mdx model of DMD suggest that CTGF contributes to the process by which muscle is replaced by fibrosis and fat and that CTGF may also impair muscle cell differentiation during muscle repair after injury.

Clinical Development of Pamrevlumab for Duchenne Muscular Dystrophy

Based on the FDA review of one year data from our Phase 2 administrative analysis, we intend to begin a Phase 3 study of pamrevlumab in non-ambulatory DMD patients in the second half of 2020.

All 21 non-ambulatory patients from our fully enrolled Phase 2 open-label single-arm trial have completed over one year of treatment with pamrevlumab.

Phase 3 Clinical Development – LELANTOS, a double-blind, placebo-controlled trial in non-ambulatory DMD patients

In the third quarter of 2020, we initiated a Phase 3 clinical trial, LELANTOS 1, evaluating pamrevlumab as a treatment for DMD.

LELANTOS 1 is a double-blind, placebo-controlled trial in approximately 90 non-ambulatory DMD patients.

Patients will be randomized at a 1:1 ratio to pamrevlumab or placebo and have a treatment period of 52 weeks.

The primary endpoint will assess change in upper limb strength and additional endpoints will include pulmonary, performance, cardiac, and fibrosis assessments.

We also plan to initiate a Phase 3 clinical trial, LELANTOS 2, evaluating pamrevlumab in 70 ambulatory DMD patients.

We expect topline data from these studies in the second half of 2022.

Phase 2 Open-Label Trial of Pamrevlumab in DMD

In June 2019 at the Parent Project Muscular Dystrophy meeting, we reported topline results from this 21 patient open-label single-arm trial in non-ambulatory DMD patients.

This one-year administrative analysis compared our Phase 2 data to previously published natural disease history studies of DMD patients.

While we cannot make direct comparisons between our trial and previously published data due to, among other things, differences in subject numbers, baseline characteristics, inclusion/exclusion criteria, treatment protocols, and analysis methods, we are encouraged by the data obtained so far.

Pamrevlumab was well tolerated in this study.

In June 2019 at the Parent Project Muscular Dystrophy meeting, we reported topline results from our one-year administrative analysis comparing our Phase 2 data to recent published natural disease history studies of DMD patients.

In pulmonary function tests, the results from our study indicate a potential reduction in the 1-year decline in FVC percent predicted from baseline for our pamrevlumab-treated patients when compared to FVC data of DMD patients (whether such patients were taking steroids or not) published in 2019 by Ricotti.

In pulmonary function tests, the results from our study indicate a potential reduction in the 1-year decline in FVC percent predicted from baseline for pamrevlumab-treated patients when compared to FVC data of DMD patients (whether such patients were taking steroids or not) published in 2019 by Ricotti.

In the 2019 Ricotti study, the DMD patients were treated with steroids only.

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In addition, pamrevlumab showed less decline in both percent predicted forced expiratory volume as compared to previously published study results of Meier in 2016, and in percent predicted peak expiratory flow rate, compared to what was observed in the study by Ricotti in 2019.

Our data showed an increase in cardiac function, measured by mean change of left ventricular ejection fraction (“LVEF”), of 0.29% from baseline for our pamrevlumab-treated patients.

Our data showed an increase in cardiac function, measured by mean change of left ventricular ejection fraction (“LVEF”), of 0.29% from baseline for pamrevlumab-treated patients.

Whereas, data published in 2018 by McDonald of DMD patients only on steroids showed a mean LVEF decline of 0.82% from baseline in one year.

In muscle function tests, the majority of the results of this Phase 2 study showed the mean change from baseline in our pamrevlumab-treated patients were more favorable than previously published data.

In muscle function tests, the majority of the results of this Phase 2 study showed the mean change from baseline in pamrevlumab-treated patients were more favorable than previously published data.

Our results showed a positive increase in grip-strength score in both dominant and non-dominant hands at one year of treatment with pamrevlumab, while earlier results from a 2015 study by Seferian showed a decline at one year as expected.

In the performance of the upper limb (“PUL”) test specifically developed for DMD patients, our pamrevlumab-treated patients had a mean change from baseline of -1.53.

In the performance of the upper limb (“PUL”) test specifically developed for DMD patients, pamrevlumab-treated patients had a mean change from baseline of -1.53.

In the 2019 study by Ricotti of DMD patients taking either nothing or only steroids, the annual mean change in the PUL test was -4.13.

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Commercialization Strategy for Pamrevlumab

Our goal, if pamrevlumab is successful, is to be a leader in the development and commercialization of novel approaches for inhibiting fibrosis and treating some forms of cancer and muscular dystrophy diseases.

Our goal, if pamrevlumab is successful, is to be a leader in the development and commercialization of novel approaches for inhibiting fibrosis and treating certain forms of cancer and muscular dystrophy diseases.

To date, we have retained exclusive worldwide rights for pamrevlumab.

We have commenced brand development activities for pamrevlumab and will be advancing these efforts in preparation for potential launches in IPF, LAPC and DMD, consistent with the approaches of companies with a product in late-stage clinical development.

Research at FibroGen

Our research programs at FibroGen are grounded in our three areas of expertise:

HIF biology, 2-oxoglutarate enzymology, and CTGF biology.

We have applied our expertise in the field of HIF-PH inhibition to develop an understanding of other areas of HIF biology with important therapeutic implications.

This consistent progression of discovery has led to findings relating to HIF-mediated effects associated with inflammatory pathways, various aspects of iron metabolism, insulin sensitivity and glucose and fat metabolism, neurological disease, and ischemic injury.

There are at least three different HIF-PH enzymes that are known to regulate the stability of HIF — these enzymes are commonly referred to in the scientific literature as PHD1, PHD2 and PHD3.

Studies of genetically modified mice, in which the individual HIF-PH enzymes have been deleted, have revealed that PHD2 plays a major role in the regulation of erythropoiesis by HIF.

In contrast, PHD1 and PHD3 appear to play less important roles in HIF-mediated erythropoiesis, but instead have been implicated in other important biological pathways.

We believe that both pan-PHD and PHD-selective inhibitors could have important therapeutic applications beyond anemia.

The HIF-PH enzymes that are the targets of roxadustat belong to a broader family of enzymes known as 2-oxoglutarate (2OG)-dependent oxygenases.

Other members of the 2OG-dependent oxygenase family with relevance to human disease include the Jumonji domain-containing histone demethylases, which are emerging cancer targets.

The fact that all members of the 2OG-dependent oxygenase enzyme family use 2OG as a co-substrate makes them viable targets for small molecule inhibitors that compete with 2OG.

FibroGen has been a leader in inhibition of enzymes belonging to this family, and our internal medicinal chemistry efforts have generated a library of novel compounds designed to target the 2OG-dependent oxygenase family.

Finally, we have applied our knowledge of CTGF to investigate additional applications of agents that interfere with the role of this protein in disease.

In some instances, we are exploring direct engagement of CTGF itself.

In other instances, we are studying the regulation of CTGF.

COLLABORATIONS

Collaboration Partnerships for Roxadustat

Our revenue to date has been generated primarily from our collaboration agreements with Astellas and AstraZeneca for the development and commercialization of roxadustat.

In addition, we started roxadustat commercial sales in China in the third quarter of 2019.

For fiscal year ended December 31, 2020, 58% of our revenue was related to our collaboration agreements, and 42% of our revenue was from roxadustat commercial sales in China.

For the fiscal years ended December 31, 2019 and 2018, substantially all of our revenue was related to our collaboration agreements.

We have two agreements with Astellas for the development and commercialization of roxadustat, one for Japan, and one for Europe, the Commonwealth of Independent States, the Middle East and South Africa.

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Astellas will be responsible for clinical development activities and all associated costs required for regulatory approval in all other countries in the Astellas territories.

Astellas will own and have responsibility for regulatory filings in its territories.

We are responsible, either directly or through our contract manufacturers, for the manufacture and supply of all quantities of roxadustat to be used in development and commercialization under the agreements.

The Astellas agreements will continue in effect until terminated.

Either party may terminate the agreements for certain material breaches by the other party.

In addition, Astellas will have the right to terminate the agreements for certain specified technical product failures, upon generic sales reaching a particular threshold, upon certain regulatory actions, or upon our entering into a settlement admitting the invalidity or unenforceability of our licensed patents.

Astellas may also terminate the agreements for convenience upon advance written notice to us.

In the event of any termination of the agreements, Astellas will transfer and assign to us the regulatory filings for roxadustat and will assign or license us the relevant trademarks used with the products in the Astellas territories.

Under certain terminations, Astellas is also obligated to pay us a termination fee.

Consideration under these agreements includes a total of $360.1 million in upfront and non-contingent payments, and milestone payments totaling $557.5 million, of which $542.5 million are development and regulatory milestones, and $15.0 million are commercial-based milestones.

Total consideration, excluding development cost reimbursement and product sales-related payments, could reach $917.6 million.

Additionally, under these agreements, Astellas pays 100% of the commercialization costs in their territories.

Astellas will pay us a transfer price for our manufacture and delivery of roxadustat based on net sales of roxadustat in the low 20% range.

Astellas will hold and have responsibility for regulatory filings in its territories.

Astellas is responsible for roxadustat commercialization activities in the Astellas territories.

We also have two agreements with AstraZeneca for the development and commercialization of roxadustat for anemia, one for China (the “China Agreement”), and one for the U.S.

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We share responsibility with AstraZeneca for clinical development activities required for U.S.

regulatory approval of roxadustat.

In 2015, we reached the $116.5 million cap on our initial funding obligations (under which we shared 50% of the initial development costs), therefore all future development and commercialization costs for roxadustat for the treatment of anemia in CKD in the U.S., Europe, Japan and all other markets outside of China will be paid by Astellas and AstraZeneca.

In China, our subsidiary FibroGen Beijing will conduct the development work for CKD anemia and will hold all of the regulatory licenses issued by China regulatory authorities and be primarily responsible for regulatory, clinical and manufacturing.

regulatory approval of roxadustat, and FibroGen will transfer the U.S.

NDA to AstraZeneca upon approval.

AstraZeneca will hold the equivalent regulatory filings in the other licensed countries.

In China, our subsidiary FibroGen (China) Medical Technology Development Co., Ltd.

(“FibroGen Beijing”) has conducted the development work for CKD anemia and will continue to hold all of the regulatory licenses issued by China regulatory authorities and be primarily responsible for regulatory, clinical and manufacturing.

China development costs are shared 50/50.

AstraZeneca is also responsible for 100% of development expenses in all other licensed territories outside of China.

We are responsible, through our contract manufacturers, for the manufacture and supply of all quantities of roxadustat to be used in development and commercialization under the agreements.

Under the AstraZeneca agreements, we receive upfront and subsequent non-contingent payments totaling $402.2 million.

Potential milestone payments under the agreements total $1.2 billion, of which $571.0 million are development and regulatory milestones, and $652.5 million are commercial-based milestones.

Total consideration under the agreements, excluding development cost reimbursement, transfer price payments, royalties and profit share, could reach $1.6 billion.

Payments under these agreements include over $500 million in upfront, non-contingent and other payments received or expected to be received prior to the first U.S.

approval, excluding development expense reimbursement.

Under the U.S./RoW Agreement, AstraZeneca will pay for all commercialization costs in the U.S.

and RoW, AstraZeneca will be responsible for the U.S.

commercialization of roxadustat, with FibroGen undertaking specified promotional activities in the ESRD segment in the U.S.

In addition, we will receive a transfer price for delivery of commercial product based on a percentage of net sales in the low- to mid-single digit range and AstraZeneca will pay us a tiered royalty on net sales of roxadustat in the low 20% range.

We are responsible, ourselves and through our contract manufacturers, for the manufacture and supply of all quantities of roxadustat to be used in development and commercialization under the AstraZeneca agreements.

Under the China Agreement, which is conducted through FibroGen China Anemia Holdings, Ltd.

(“FibroGen China”), the commercial collaboration is structured as a 50/50 profit share.

AstraZeneca will conduct sales and marketing activities in China for roxadustat and will fund roxadustat launch costs in China until FibroGen Beijing has achieved profitability.

At that time, AstraZeneca will recoup 50% of their historical launch costs out of initial roxadustat profits in China.

AstraZeneca may terminate the U.S./RoW Agreement upon specified events, including our bankruptcy or insolvency, our uncured material breach, technical product failure, or upon 180 days prior written notice at will.

If AstraZeneca terminates the U.S/RoW Agreement at will, in addition to any unpaid non-contingent payments, it will be responsible to pay for a substantial portion of the post-termination development costs under the agreed development plan until regulatory approval.

AstraZeneca may terminate the China Agreement upon specified events, including our bankruptcy or insolvency, our uncured material breach, technical product failure, or upon advance prior written notice at will.

If AstraZeneca terminates our China Agreement at will, it will be responsible to pay for transition costs as well as make a specified payment to FibroGen China.

In the event of any termination of the agreements, but subject to modification upon termination for technical product failure, AstraZeneca will transfer and assign to us any regulatory filings and approvals for roxadustat in the affected territories that they may hold under our agreements, grant us licenses and conduct certain transition activities.

(“FibroGen Cayman”), FibroGen Beijing, and FibroGen International (Hong Kong) Limited (collectively, “FibroGen China”), the commercial collaboration is structured as a 50/50 profit share, which was restructured in the third quarter of 2020.

Pursuant to an Amendment to the China Agreement, t he parties agreed to establish a jointly owned entity to conduct distribution.

FibroGen Beijing will manufacture and transfer commercial product to the distribution entity in exchange for a transfer price at a percentage of net sales.

AstraZeneca will conduct sales and marketing activities in China for roxadustat, which will be billed to the distribution entity, subject to a cap of a percentage of roxadustat net sales until AstraZeneca has recouped its sales and marketing expenses, at which time it will bill actual expenses, subject to the cap.

Additional Information Related to Collaboration Agreements

Additional information related to collaboration agreements is set forth in Item 7 of this Annual Report on Form 10-K.

Information about collaboration partners that accounted for more than 10% of our total revenue or accounts receivable for the last three fiscal years is set forth in Note 14 to our consolidated financial statements under Item 8 of this Annual Report.

Additional information related to our collaboration agreements is set forth in Item 7 of this Annual Report on Form 10-K, and Note 4, Collaboration Agreements and Revenues, to our consolidated financial statements under Item 8 of this Annual Report.

Information about collaboration partners that accounted for more than 10% of our total revenue or accounts receivable for the last three fiscal years is set forth in Note 15, Segment and Geographic Information , to our consolidated financial statements under Item 8 of this Annual Report.

The pharmaceutical and biotechnology industries are highly competitive, particularly in some of the indications we are developing drug candidates, including anemia in CKD, IPF, pancreatic cancer, and DMD.

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These potential advantages of our competitors are particularly a risk in IPF, pancreatic cancer, and DMD, where we do not currently have a development or commercialization partner.

We expect any products that we develop and commercialize to compete on the basis of, among other things, efficacy, safety, convenience of administration and delivery, price, the level of generic competition, and the availability of reimbursement from government and other third-party payors.

When any of our product candidates are approved, they will compete with currently marketed products, and product candidates that may be approved for marketing in the future, for treatment of the following indications:

Roxadustat — Anemia in CKD

We expect any products that we develop and commercialize to compete based on, among other things, efficacy, safety, convenience of administration and delivery, price, the level of generic competition, and the availability of reimbursement from government and other third-party payors.

In addition, we will likely face competition from other companies developing treatments of other anemia indications that we may also seek to pursue in the future or that may be sold in indications we are pursuing but for which they are not yet approved.

We may face competition for patient recruitment, enrollment for clinical trials, and potentially in commercial sales.

There may also be new therapies for renal-related diseases that could limit the market or level of reimbursement available for roxadustat.

Approved Medicines

Drugs that will compete with roxadustat are expected to include ESAs, particularly in those patient segments where ESAs are used.

Currently available ESAs include epoetin alfa (EPOGEN ® marketed by Amgen Inc.

Some of the available ESAs include epoetin alfa (EPOGEN ® marketed by Amgen Inc.

in the U.S., Procrit ® and Erypo ® /Eprex ® , marketed by Johnson & Johnson, Inc.

and Espo ® marketed by Kyowa Hakko Kirin in Japan and China), darbepoetin (Amgen/Kyowa Hakko Kirin’s Aranesp ® and NESP ® ) and Mircera ® marketed by Roche outside the U.S.

and by Vifor Pharma (“Vifor”), a Roche licensee, in the U.S.

and by Vifor Pharma, a Roche licensee, in the U.S.

and Puerto Rico, as well as biosimilar versions of these currently marketed ESA products.

ESAs have been used in the treatment of anemia in CKD for more than 30 years, serving a significant majority of dialysis patients.

While non-dialysis CKD patients who are not under the care of nephrologists, including those with diabetes and hypertension, do not typically receive ESAs and are often left untreated, some patients under nephrology care may be receiving ESA therapy.

While non-dialysis CKD anemia patients who are not under the care of nephrologists, including those with diabetes and hypertension, do not typically receive ESAs and are often left untreated, some patients under nephrology or hematology care may be receiving ESA therapy.

It may be difficult to encourage healthcare providers and patients to switch to roxadustat from products with which they have become familiar.

We may also face competition from potential new anemia therapies currently in clinical development, including in those patient segments not currently addressed by ESAs.

The first biosimilar ESA, Pfizer’s Retacrit® (epoetin zeta), entered the U.S.

market in November 2018.

Market penetration of Retacrit and the potential addition of other biosimilar ESAs currently under development may alter the competitive and pricing landscape of anemia therapy in CKD patients on dialysis under the end-stage renal disease bundle.

The patents for Amgen’s EPOGEN ® (epoetin alfa) expired in 2004 in Europe, and the final material patents in the U.S.

expired in May 2015.

Several biosimilar versions of currently marketed ESAs are available for sale in Europe, China and other territories.

In the U.S., a few ESA biosimilars are currently under development.

Sandoz, a division of Novartis, markets Binocrit® (epoetin alfa) in Europe and may file a biosimilar Biologics License Application in the U.S.

Product Candidates in Development

We may also face competition from potential new anemia therapies currently in clinical development, including in those patient segments not adequately addressed by ESAs.

Companies that are currently developing HIF-PH inhibitors for anemia in CKD indications include GlaxoSmithKline plc (“GSK”), Bayer Corporation (“Bayer”), Akebia Therapeutics, Inc.

(“Akebia”), Japan Tobacco, and Zydus Cadila.

Akebia is currently conducting Phase 3 studies in CKD patients on dialysis and not on dialysis, as well as a Phase 2 study evaluating pharmacokinetics and pharmacodynamics in dialysis-dependent patients with three-times weekly versus once-a-day dosing.

Akebia expects to complete these studies by August 2020.

In Japan, Mitsubishi Tanabe Pharmaceutical Corporation, Akebia’s collaboration partner, submitted an NDA for treatment of anemia in dialysis and non-dialysis CKD patients in July 2019, and is awaiting an approval decision later in 2020.

(“Akebia”), Otsuka Pharmaceutical (“Otsuka”), Akebia’s partner in the U.S.

and Europe, Japan Tobacco, and Zydus Cadila (India) (“Zydus”).

Akebia has completed Phase 3 studies in CKD patients on dialysis and not on dialysis in the U.S., as well as a Phase 3b, randomized, open-label, active-controlled trial evaluating the efficacy and safety of oral vadadustat once daily and three times weekly for the maintenance treatment of anemia in hemodialysis subjects converting from erythropoiesis stimulating agents.

The study completion date is estimated to be May 2022.

Akebia announced an additional Phase 3 study evaluating the efficacy and safety of dose conversion from a long-acting erythropoiesis stimulating agent (Mircera®) to three times weekly oral vadadustat for the maintenance treatment of anemia in hemodialysis subjects.

The estimated study start date is February 2021.

Akebia has publicly stated their intent to file the vadadustat NDA in the U.S.

in the second quarter of 2021.

In Japan, Mitsubishi Tanabe Pharmaceutical Corporation, Akebia’s collaboration partner, received approval for vadadustat on June 29, 2020 for the treatment of anemia of CKD patients on and not on dialysis.

GSK received approval for daprodustat in Japan on June 29, 2020 for the treatment of anemia of CKD patients on and not on dialysis.

Price listing for the launch in Japan of both vadadustat and daprodustat occurred in the third quarter of 2020, with pricing in line with roxadustat pricing.

GSK is also conducting global Phase 3 studies in CKD patients on dialysis and not on dialysis, and expects to complete those studies by March 2022.

GSK and Kyowa Hakko Kirin announced in November 2018 that the two companies signed a strategic commercialization deal in Japan for daprodustat.

GSK submitted a Japan NDA for treatment of anemia in dialysis and non-dialysis in August 2019 and is awaiting approval later in 2020.

Bayer has completed global Phase 2 studies and its HIF-PH inhibitor is now in Phase 3 development in CKD populations on dialysis and not on dialysis in Japan.

Japan Tobacco submitted an NDA for treatment of anemia associated with CKD in Japan in November 2019, supported by the six Phase 3 studies conducted in CKD patients on dialysis and not on dialysis in Japan, and its partner JW Pharmaceuticals started a Phase 3 study in dialysis patients in Korea.

Zydus Cadila (India) started Phase 3 studies in dialysis and non-dialysis CKD patients in India in 2019.

In addition, there are other companies developing biologic therapies for the treatment of other anemia indications that we may also seek to pursue in the future, including anemia of MDS.

For example, Acceleron Pharma, Inc., in partnership with Celgene Corporation, a Bristol-Myers Squibb company (“Celgene”), developed Reblozyl® (luspatercept), a protein therapeutic, which was approved in November 2019 by the FDA for anemia treatment in patients with ß-thalassemia.

Its Biologics License Application (“BLA”) under review by the FDA, for treatment of adult patients with very low to intermediate MDS associated anemia who have ring sideroblast and require red blood cell transfusions, has a Prescription Drug User Fee Act date of April 4, 2020.

Acceleron expects an EMA decision on the MAA in the second half of 2020.

In Japan, Celgene started a luspatercept Phase 2 study in May 2019.

We may face competition for patient recruitment, enrollment for clinical trials, and potentially in commercial sales.

There may also be new therapies for renal-related diseases that could limit the market or level of reimbursement available for roxadustat if and when it is commercialized.

Japan Tobacco received approval in Japan for enarodustat for the treatment of anemia in CKD patients on dialysis and not on dialysis, to be sold by Torii Pharmaceuticals Ltd as ENAROY ® .

Japan Tobacco and its partner JW Pharmaceuticals started a Phase 3 study in dialysis patients in Korea in 2019.

Zydus started Phase 3 studies in dialysis and non-dialysis CKD patients in India in 2019.

In China, biosimilars of epoetin alfa are offered by Chinese pharmaceutical companies such as EPIAO marketed by 3SBio Inc.

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has submitted a clinical trial application to the NMPA to initiate trials for their HIF-PH inhibitor.

Another domestic company, China Medical System, in-licensed desidustat, a compound which is currently in Phase 3 trials in India, from Zydus Candila for greater China in January 2020.

Akebia announced in December 2015 that it had entered into a development and commercialization partnership with Mitsubishi Tanabe Pharmaceutical Corporation for its HIF-PH inhibitor vadadustat in Japan, Taiwan, South Korea, India and certain other countries in Asia , and announced in April 2017 an expansion of their U.S.

Another domestic company, China Medical System Holdings Ltd., in-licensed desidustat, a compound that is currently in Phase 3 trials in India, from Zydus for greater China in January 2020.

In January 2021, China Medical System Holdings Ltd.

was granted approval by the NMPA in China to begin trials for desidustat in patients with anemia of CKD, including dialysis and non-dialysis patients.

Shenzhen Salubris Pharmaceutical Co., Ltd., a domestic company in China, has in-licensed enarodustat from Japan Tobacco and received NMPA approval in the third quarter of 2020 to initiate Phase 3 studies.

Akebia announced in April 2017 an expansion of their U.S.

collaboration with Otsuka to add markets, including China.

announced in 2016 its plan to begin a Phase 1 clinical trial of a HIF-PH inhibitor for the China market.

The first biosimilar ESA, Pfizer’s Retacrit® (epoetin zeta), entered the U.S.

market in November 2018.

The patents for Amgen’s EPOGEN ® (epoetin alfa) expired in 2004 in the Europe, and the final material patents in the U.S.

expired in May 2015.

Several biosimilar versions of currently marketed ESAs are available for sale in the Europe, China and other territories.

In the U.S., a few ESA biosimilars are currently under development.

Sandoz, a division of Novartis, markets Binocrit® (epoetin alfa) in Europe and may file a biosimilar BLA in the U.S.

In July 2020, Zydus received approval from the FDA to begin a Phase 1 study of desidustat for the treatment of CIA, which could potentially be competitive with roxadustat within this indication.

It is the first and only erythroid maturation agent approved in the U.S., Europe, and Canada and is part of a global collaboration between Acceleron Pharma, Inc.

and Bristol Myers Squibb.

In 2020, Reblozyl net revenue was $274 million, including $115 million in Q4 2020.

Large Dialysis Organizations

The majority of the current CKD anemia market focuses on dialysis patients, who visit dialysis centers on a regular basis, typically three times a week, and anemia therapies are administered as part of the visit.

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KGaA (“Fresenius”), collectively provide dialysis care to more than 80% of U.S.

dialysis patients, and therefore have historically won long-term contracts including rebate terms with Amgen.

dialysis patients, and therefore have historically secured long-term contracts including rebate terms with Amgen.

DaVita has a six-year sourcing and supply agreement with Amgen effective through 2022.

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dialysis patients.

Successful penetration in this market may require a significant agreement with Fresenius or DaVita, on favorable terms and on a timely basis.

We are currently in Phase 2 development of pamrevlumab to treat DMD and Phase 3 development of pamrevlumab in IPF and pancreatic cancer.

Most of our competitors have significantly more resources and expertise in development, commercialization and manufacturing, particularly due to the fact that we have not yet established a co-development partnership for pamrevlumab.

Successful penetration in this market may require our partner AstraZeneca to enter into an agreement with Fresenius, DaVita, or other dialysis organizations, on favorable pricing terms to each party.

We are currently in Phase 3 development of pamrevlumab in IPF, locally advanced pancreatic cancer, and DMD.

For example, both Roche and Boehringer Ingelheim, which market products for the treatment of IPF in the U.S., have successfully developed and commercialized drugs in various indications and have built sales organizations that we do not currently have;

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We believe that if pamrevlumab can be shown to safely stabilize or reverse lung fibrosis, and thus stabilize or improve lung function in IPF patients, it can compete with pirfenidone and nintedanib for market share in IPF.

However, it may be difficult to encourage treatment providers and patients to switch to pamrevlumab from a product they are already familiar with.

However, it may be difficult to encourage treatment providers and patients to switch to pamrevlumab from a product with which they are already familiar.

We may also face competition from potential new IPF therapies in recruitment and enrollment in our clinical trials and potentially in commercialization.

Pamrevlumab is an injectable protein, which may be more expensive and less convenient than small molecules such as nintedanib and pirfenidone.

Other potential competitive product candidates in various stages of development for IPF include Galapagos NV’s GLPG1690 and GLPG1205, Kadmon Holdings, Inc.’s KD025, Liminal BioSciences’ PBI-4050, and Roche/Promedior, Inc.’s PRM-151.

In particular, GLPG1690 is in a Phase 3 program consisting of two clinical trials with 750 subjects each, intended to support both the U.S.

NDA and MAA in Europe.

Pamrevlumab is administered via infusion, which may be more expensive and less convenient than small molecules such as nintedanib and pirfenidone.

Other potential competitive product candidates in various stages of development for IPF include Kadmon Holdings, Inc.’s KD025, Liminal BioSciences’ PBI-4050, and Roche/Promedior, Inc.’s PRM-151.

Pancreatic Cancer

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Duchenne Muscular Dystrophy

If approved and launched commercially to treat DMD, pamrevlumab is expected to face competition from drugs that have been approved in major markets such as the U.S., EU, and Japan.

If approved and launched commercially to treat DMD, pamrevlumab is expected to face competition from drugs that have been approved in major markets such as the U.S., European Union, and Japan.

On September 19, 2016, the FDA approved Sarepta Therapeutics Inc.’s (“Sarepta”) Exondys 51 TM (eteplirsen).

This was the first drug approved to treat DMD.

Exondys 51 is approved to treat patients who have a mutation of the dystrophin gene amenable to exon 51 skipping, representing approximately 13% of patients with DMD.

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Sarepta has reported a full year Exondys 51 revenue of $380 million in 2019.

Sarepta’s Vyondys 53 TM (golodirsen) was also approved by the FDA in December 2019 for patients with a confirmed genetic mutation that is amenable to exon 53 skipping, which accounts for 8% of the DMD population.

Sarepta’s Vyondys 53 TM (golodirsen) was approved by the FDA in December 2019 for patients with a confirmed genetic mutation that is amenable to exon 53 skipping, which accounts for approximately 8% of the DMD population.

Sarepta’s Amondys 45™ (casimersen) was approved by the FDA in February 2021 for patients with a confirmed genetic mutation that is amenable to exon 45 skipping, which accounts for approximately 8% of the DMD population.

PTC Therapeutics’ product Translarna TM received a conditional approval in Europe in 2014, which was renewed in November 2016 with a request for a new randomized placebo-controlled 18-month study by the Committee for Medicinal Products for Human Use of the EMA;

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Pamrevlumab may also face competition from other drugs currently in clinical development in patient recruiting and enrollment in clinical trials, and, if approved, in commercialization.

Examples of those compounds currently under clinical development are the drug candidates from Catabasis Pharmaceuticals (“ Catabasis”), Santhera Pharmaceuticals (“Santhera”) and Sarepta.

Catabasis’ edasalonexent was reported to have preserved muscle function and slowed the progression of DMD compared to rates of change in the control period prior to treatment with edasalonexent in a Phase 2 study, and is currently undergoing Phase 3 development.

Santhera’s Puldysa® (idebenone) MAA for treatment of DMD was filed with the EMA, and the opinion from the Committee for Medicinal Products for Human Use is expected in the second quarter of 2020.

The FDA requested additional clinical data from the idebenone Phase 3 trial currently ongoing in the U.S.

Santhera offers compassionate use of idebenone in patients with DMD in U.S.

Sarepta’s SRP-9001 is an investigational gene therapy for DMD.

Sarepta announced in December 2019 the licensing agreement with Roche that grants Roche the commercial rights to SRP-9001 outside the U.S .

Examples of those compounds currently under clinical development are the drug candidates from Catabasis Pharmaceuticals, Santhera Pharmaceuticals, and Sarepta.

MANUFACTURE AND SUPPLY

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Roxadustat is a small-molecule drug manufactured from generally available commercial starting materials and chemical technologies and multi-purpose equipment available from many third party contract manufacturers.

Outside of China, we plan to continue to use, Shanghai SynTheAll Pharmaceutical Co., Ltd.

We have entered into commercial supply arrangements with Shanghai SynTheAll Pharmaceutical Co., Ltd.

(“WuXi STA”) and Catalent, Inc.

(“Catalent”) as our primary manufacturers of roxadustat drug substance (also known as active pharmaceutical ingredient or “API”) and roxadustat drug product, respectively.

WuXi STA is located in China and currently supplies our API globally except for China, for which it manufactures an intermediate to be further manufactured by FibroGen China.

WuXi STA is located in China and currently supplies our API globally except for China, for which it manufactures an intermediate to be further manufactured by FibroGen Beijing.

WuXi STA has passed inspections by several regulatory agencies, including the FDA and NMPA, and is Current Good Manufacturing Practice (“cGMP”) compliant.

Catalent is located in the U.S.

and supplies our drug product tablets globally except for Japan, where they are manufactured by Astellas, and China, where they are manufactured by FibroGen China.

and supplies our drug product tablets globally except for Japan, where they are manufactured by Astellas, and China, where they are manufactured by FibroGen Beijing.

Catalent has passed several regulatory inspections, including by the FDA, and manufactures commercial products for other clients.

To date, we believe that roxadustat has been manufactured under cGMP and in compliance with applicable regulatory requirements for the manufacture of drug substance and drug product used in clinical trials and we and Astellas have performed audits of the existing roxadustat manufacturers.

The intended commercial manufacturing route outside of China has been successfully scaled up to multiple hundred kilogram scale and produced several metric tons of roxadustat drug substance.

We are in discussions with multiple parties regarding longer term commercial supply arrangements.

In China, our Beijing facility received the Good Manufacturing Practice (“GMP”) license for API and drug product.

We are manufacturing drug product at our FibroGen Beijing manufacturing facility for commercial supply.

We are manufacturing drug product at our FibroGen Beijing manufacturing facility for commercial supply, but we are not currently manufacturing API at this facility.

We are manufacturing API at our Cangzhou manufacturing facility, which has been fully qualified and licensed.

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Any agreement would provide that no minimum amounts would be specified until appropriate by forecast, that we and our commercialization partner would have the rights to contract with independent third parties that exceed IRIX’s internal capabilities or in the event that we or our commercialization partner determines for reasons of continuity and security that such a need exists, provided that IRIX would supply a majority of the product if it is able to meet the requirements and the schedule required by us and our partner.

Subsequent to the Letter of Agreement, we and IRIX have entered into several additional service agreements.

Subsequent to the Letter of Agreement, IRIX and we have entered into several additional service agreements.

IRIX has requested in writing that we honor the Letter of Agreement with respect to the single source manufacturing agreement.

To date, we have offered to IRIX opportunities to bid for the manufacture of HIF-PH inhibitors, including roxadustat.

In 2015, Patheon Pharmaceuticals Inc., a business unit of DPx Holdings B.V.

(“Patheon”), acquired IRIX, and in 2017 ThermoFisher Scientific Inc.

acquired Patheon.

To date, pamrevlumab has been manufactured using specialized biopharmaceutical process techniques under an agreement with a qualified third party contract manufacturer, Boehringer Ingelheim.

Our contract manufacturer is the sole source for the current clinical supply of the drug substance and drug product for pamrevlumab.

Our contract manufacturer is only obligated to supply the amounts of pamrevlumab as agreed on pursuant to work orders that are executed from time to time under our agreement as we determine need for clinical material, and we are not required to make fixed or minimum annual purchases.

Our existing agreement allows us to transfer the cell line manufacturing process to another third party manufacturer at our expense, and our contractor is obligated to provide reasonable technology transfer assistance in the event of such a transfer.

In 2015, Patheon Pharmaceuticals Inc., a business unit of DPx Holdings B.V., acquired IRIX, and in 2017 ThermoFisher Scientific Inc.

acquired Patheon Pharmaceuticals Inc.

To date, pamrevlumab has been manufactured using specialized biopharmaceutical process techniques under a clinical supply agreement with a qualified third party contract manufacturer, Boehringer Ingelheim.

We have entered into a clinical and commercial supply agreement for the manufacture of pamrevlumab with Samsung Biologics Co., Ltd., which has passed several regulatory inspections, including by the FDA, and manufactures commercial products for other clients.

GOVERNMENT REGULATION

The clinical testing, manufacturing, labeling, storage, distribution, record keeping, advertising, promotion, import, export and marketing, among other things, of our product candidates are subject to extensive regulation by governmental authorities in the U.S.

and other countries.

Our business activities and operations, including the clinical testing, manufacturing, labeling, storage, distribution, record keeping, advertising, promotion, import, export and marketing of our product candidates, among other things, are subject to extensive regulation by governmental authorities in the U.S., China, and other countries.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations, including in Europe and China, requires the expenditure of substantial time and financial resources.

Compliance with environmental laws, rules, and regulations has not had, and is not expected to have, a material effect on our capital expenditures, results of operations, or competitive position, and we do not currently anticipate material capital expenditures for environmental control facilities.

Failure to comply with the applicable requirements at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including refusal by the applicable regulatory authority to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by FDA and the Department of Justice, or other governmental entities.

We cannot predict with certainty whether future costs of compliance with government regulations, including any changes thereto or reinterpretations thereof, will have a material impact on capital expenditures, earnings or the company’s competitive position.

Refer to the section of this Annual Report captioned “ Item 1A.

Risk Factors ” for a discussion of these potential impacts.

Product Approval Process

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The submission to the FDA of an IND for human clinical testing, which must become effective before each human clinical trial commence.

Adequate and well-controlled human clinical trials to establish the safety and efficacy of the product and conducted in accordance with Good Clinical Practices.

Adequate and well-controlled human clinical trials to establish the safety and efficacy of the product and conducted in accordance with good clinical practices (“GCP”).

The submission to the FDA of an NDA, in the case of a small molecule drug product, or a BLA, in the case of a biologic product.

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This in turn could affect our ability to successfully commercialize our products and impact our profitability, results of operations, financial condition and future success.

In addition, in many foreign countries, particularly the countries of the Europe and China, the pricing of prescription drugs is subject to government control.

In addition, in many foreign countries, particularly the countries of the European Union and China, the pricing of prescription drugs is subject to government control.

In some non-U.S.

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The requirements governing drug pricing vary widely from country to country.

For example, the Europe provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

For example, the European Union provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use.

A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of a company placing the medicinal product on the market.

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Any proposed or actual changes could limit or eliminate our spending on development projects and affect our ultimate profitability.

Under the Medicare Improvements for Patients and Providers Act (“MIPPA”), a basic case-mix adjusted composite, or bundled, payment system commenced in January 2011 and transitioned fully by January 2014 to a single reimbursement rate for drugs and all services furnished by renal dialysis centers for Medicare beneficiaries with end-stage renal disease.

Specifically, under MIPPA the End-Stage Renal Disease Prospective Payment System (the “ESRD PPS”) bundle now covers drugs, services, lab tests and supplies under a single treatment base rate for reimbursement by the CMS based on the average cost per treatment, including the cost of ESAs and IV iron doses, typically without adjustment for usage.

It is unknown whether roxadustat, if approved in the U.S., will be included in the payment bundle or the timing of inclusion.

Under MIPPA, agents that have no IV equivalent in the bundle are currently expected to be excluded from the bundle until 2025.

If roxadustat were included in the bundle, it may reduce the price that could be charged for roxadustat, and therefore potentially limit our profitability.

Based on roxadustat’s differentiated mechanism of action and therapeutic effects, and discussions with our collaboration partner, we currently believe that roxadustat might not initially be included in the bundle and would instead be eligible for a Transitional Drug Add-on Payment Adjustment (“TDAPA”) for a 24-month period.

At the 24-month mark, CMS would determine if the TDAPA period should be extended for roxadustat or ended.

When the TDAPA period ends, CMS will determine if roxadustat should be included in the bundle and, if so, what changes to the ESRD PPS reimbursement should be made.

If roxadustat is included in the ESRD PPS bundle, it may have an impact on roxadustat pricing within Dialysis Organizations.

If roxadustat is not included in the bundle after the TDAPA period, and would therefore be reimbursed outside of the bundle, it may potentially limit further market penetration of roxadustat.

In March 2010, PPACA was signed into law.

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and extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed care organizations.

There remain judicial and Congressional challenges to certain aspects of the PPACA.

Supreme Court is currently reviewing the constitutionality of the PPACA, but it is unknown when a decision will be reached.

It is unclear how the U.S.

Supreme Court ruling, other such litigation, and the healthcare reform measures of the Biden administration will impact the PPACA.

In the future, there may continue to be additional proposals relating to the reform of the U.S.

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Managed care organizations, as well as Medicaid and other government agencies, continue to seek price discounts.

Further, in the U.S.

there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under government payor programs, and review the relationship between pricing and manufacturer patient programs.

At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing that attempt to implement several of the administration’s proposals.

The FDA also released a final rule, effective November 30, 2020, implementing a portion of the importation executive order providing guidance for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed pending review by the Biden administration until March 22, 2021.

On November 20, 2020, CMS issued an interim final rule implementing President Trump’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

On December 28, 2020, the United States District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule.

However, it is unclear whether the Biden administration will work to reverse these measures or pursue similar policy initiatives.

Some states have implemented, and other states are considering, price controls or patient access constraints under the Medicaid program, and some states are considering price-control regimes that would apply to broader segments of their populations that are not Medicaid-eligible.

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Such policy actions could have a material adverse impact on our profitability.

Regulation in China

Approval Process and Other Regulation in China

The pharmaceutical industry in China is highly regulated.

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Drugs fall into one of three categories, namely chemical medicine, biological product or traditional Chinese or natural medicine.

Our roxadustat NDA for treatment of CKD anemia was submitted by FibroGen Beijing as a domestic entity under the Domestic Class 1 designation, which refers to a new drug which has never been marketed in any country.

Our roxadustat NDA for treatment of CKD anemia was submitted by FibroGen Beijing as a domestic entity under the Domestic Class 1 designation, which refers to a new drug that has never been marketed in any country.

Our NDA package in China contained information similar to what is necessary for a U.S.

NDA, including preclinical data, clinical data, technical data on API and drug product, and related stability data.

The NDA package was found acceptable to the NMPA, and FibroGen Beijing was granted a New Drug License confirming the drug as suitable for marketing in December 2018.

In addition, FibroGen Beijing was granted a Manufacturing License which lists the Drug Approval Code as well as the name and address of the Manufacturing License holder.

We are currently performing a safety study of 2,000 patients who will be treated for 52 weeks as part of our post-approval commitment to the NMPA.

Shortly before NDA approval, FibroGen Beijing conducted a three-batch validation campaign, one of which was observed onsite by the NMPA.

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Foreign Regulation Outside of China

We have received marketing authorization for roxadustat in Japan for anemia of CKD in dialysis patients, and in China for dialysis and non-dialysis patients.

Astellas has submitted a supplemental NDA for non-dialysis patients in Japan and intends on submitting an MAA for Europe in the first half of 2020.

Our partners also intend to submit for marketing authorization in other countries and we may file for marketing authorization for pamrevlumab or roxadustat in other indications and in other countries in the future.

In order to market any product outside of the U.S., we would need to comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, manufacturing, marketing authorization, commercial sales and distribution of our products.

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A CTA must be submitted to each national health authority and an independent ethics committee.

For other countries outside of the Europe, such as China and the countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing, and reimbursement vary from country to country.

For other countries outside of the European Union, such as China and the countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing, and reimbursement vary from country to country.

The time required to obtain approval in other countries and jurisdictions might differ from or be longer than that required to obtain FDA approval.

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Orphan Drug Act

Pamrevlumab has received orphan drug designation in IPF , locally advanced unresectable pancreatic cancer, and DMD in the U.S.

Pamrevlumab has received orphan drug designation in IPF, LAPC, and DMD in the U.S.

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the U.S., or if it affects more than 200,000 individuals in the U.S.

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If a drug product designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan product exclusivity in any indication.

T he EMA has granted Orphan Medicinal Product Designation to pamrevlumab for the treatment of DMD.

Orphan Medicinal Product D esignation status in the Europe has similar but not identical benefits in that jurisdiction.

Products receiving orphan designation in the Europe can receive ten years of market exclusivity, during which time no similar medicinal product for the same indication may be placed on the market.

The EMA has granted Orphan Medicinal Product Designation to pamrevlumab for the treatment of DMD.

Orphan Medicinal Product Designation status in Europe has similar but not identical benefits in that jurisdiction.

Products receiving orphan designation in Europe can receive ten years of market exclusivity, during which time no similar medicinal product for the same indication may be placed on the market.

The ten-year market exclusivity may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation;

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or the initial applicant cannot supply enough orphan medicinal product.

An orphan product can also obtain an additional two years of market exclusivity in the Europe for pediatric studies.

An orphan product can also obtain an additional two years of market exclusivity in Europe for pediatric studies.

No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.

Foreign Country Data Exclusivity

The Europe also provides opportunities for additional market exclusivity.

For example, in the Europe, upon receiving marketing authorization, an NCE generally receives eight years of data exclusivity and an additional two years of market exclusivity.

If granted, data exclusivity prevents regulatory authorities in the Europe from referencing the innovator’s data to assess a generic application.

Europe also provides opportunities for additional market exclusivity.

For example, in Europe, upon receiving marketing authorization, an NCE generally receives eight years of data exclusivity and an additional two years of market exclusivity.

If granted, data exclusivity prevents regulatory authorities in Europe from referencing the innovator’s data to assess a generic application.

During the additional two-year period of market exclusivity, a generic marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic product can be marketed until the expiration of the market exclusivity.

In China, there is also an opportunity for data exclusivity for a period of six years for data included in an NDA applicable to a NCE.

According to the Provisions for Drug Registration, the Chinese government protects undisclosed data from drug studies and prevents the approval of an application made by another company that uses the undisclosed data for the approved drug.

In addition, if an approved drug manufactured in China qualifies as an innovative drug, such as Domestic Class 1, and the NMPA determines that it is appropriate to protect public health with respect to the safety and efficacy of the approved drug, the NMPA may elect to monitor such drug for up to five years.

During this post-marketing observation period, the NMPA will not grant approval to another company to produce, change dosage form of or import the drug while the innovative drug is under observation.

According to the Implementing Regulations of the PRC Drug Administration Law, the Chinese government protects undisclosed data from drug studies and prevents the approval of an application made by another company that uses the undisclosed data for the approved drug.

In practice, the NMPA has not established an effective mechanism to enforce data exclusivity.

The NMPA issued a draft regulation on regulatory data protection on April 25, 2018 for public comments but this draft regulation has yet to be finalized and implemented.

In addition, if an approved drug manufactured in China qualifies as an innovative drug or an improved new drug before December 1, 2019, such drugs will be eligible for a monitoring surveillance period for up to five years.

During this post-marketing observation period, the NMPA will not accept marketing authorization applications filed by another company for the same product.

Nor will the NMPA approve marketing authorization applications filed by another company to produce, change dosage form of or import the drug while the innovative or improved new drug is under observation for the purpose of protecting public health.

The approved manufacturer is required to provide an annual report to the regulatory department of the province, autonomous region or municipality directly under the central government where it is located.

Each of the data exclusivity period and the observation period runs from the date of approval for production of the NCE or innovative drug, as the case may be.

Each of the data exclusivity period and the observation period runs from the date of approval for production of the NCE or innovative or improved new drug, as the case may be.

INTELLECTUAL PROPERTY

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Our ability to maintain and solidify our proprietary position for our products and core technologies will depend on our success in obtaining effective claims and enforcing those claims once granted.

We have been in the past and are currently involved in various administrative proceedings with respect to our patents and patent applications and may, as a result of our extensive portfolio, be involved in such proceedings in the future.

Additionally, in the future, we may claim that a third party infringes our intellectual property or a third party may claim that we infringe its intellectual property.

In any of the administrative proceedings or in litigation, we may incur significant expenses, damages, attorneys’ fees, costs of proceedings and experts’ fees, and management and employees may be required to spend significant time in connection with these actions.

We have been in the past and are currently involved in various legal proceedings with respect to our patents and patent applications and may, as a result of our extensive portfolio, be involved in such proceedings in the future.

Additionally, we may claim that a third party infringes our intellectual property or a third party may claim that we infringe its intellectual property.

Such legal proceedings may be associated with significant expenses, damages, attorneys’ fees, costs of proceedings and experts’ fees, and management and employees may be required to spend significant time in connection with these actions.

Because of the extensive time required for clinical development and regulatory review of a product candidate we may develop, it is possible that any patent related to our product candidates may expire before any of our product candidates can be commercialized, or may remain in force for only a short period of time following commercialization, thereby reducing the advantage afforded by any such patent.

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patents relating to the composition-of-matter of roxadustat are due to expire in 2024 or 2025, and granted foreign patents are due to expire in 2024.

and foreign patents relating to crystalline forms of roxadustat are due to expire in 2033 .

Oppositions were filed against our European Patent No.

2872488 (the “`488 Patent”), which claims a crystalline form of roxadustat.

Final resolution of the opposition proceedings will take time, and we cannot be assured of the breadth of the claims that will remain in the ’488 Patent or that the patent will not be revoked in its entirety.

and foreign patents relating to crystalline forms of roxadustat are due to expire in 2033, and U.S.

and foreign patents relating to photostable formulations of roxadustat are due to expire in 2034.

In 2020, oppositions were filed against our European Patent No.

2872488 (the “`488 Patent”), which claims a crystalline form of roxadustat, and our European Patent No.

3003284 (the “`284 Patent”), which claims photostable formulations of roxadustat.

Final resolution of the opposition proceedings will take time and we cannot be assured that all or any claims will remain.

We believe that, if roxadustat is approved, a full five-year patent term extension under the Hatch-Waxman act will be available for a granted U.S.

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Patents relating to roxadustat composition-of-matter and crystalline forms are due to expire in 2024 and 2033, respectively.

We believe that roxadustat, as a new chemical entity, would be eligible for six years of data exclusivity in China.

Furthermore, upon approval as a new drug, roxadustat may receive up to five years of market exclusivity under a NMPA-imposed new drug monitoring period.

Refer to “Government Regulation — Regulatory Exclusivity for Approved Products — Foreign Country Data Exclusivity.”

HIF Anemia-Related Technologies Patent Portfolio

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This portfolio currently contains granted patents and pending patent applications providing exclusivity for use of compounds falling within various and overlapping classes of HIF-PH inhibitors to achieve various therapeutic effects.

This portfolio reflects a series of discoveries we made from the initial days of our HIF program through the present time.

Our research efforts have resulted in progressive innovation, and the corresponding patents and patent applications reflect the success of our HIF program.

Such discoveries include the ability of HIF-PH inhibitors:

To induce endogenous EPO in CKD patients with anemia.

To increase efficacy of EPO signaling.

To enhance EPO responsiveness of the bone marrow, for example, by increasing EPO receptor expression.

To overcome the suppressive and inhibitory effects of inflammatory cytokines, such as members of the interleukin-1 and IL-6 cytokine families, on EPO production and responsiveness .

To increase effective metabolism of iron.

To increase iron absorption and bioavailability, as measured using clinical parameters such as percent TSAT%.

To overcome iron deficiency through effects on iron regulatory factors such as ferroportin and hepcidin.

To provide coordinated erythropoiesis resulting in increased CHr and increased mean corpuscular volume.

To improve kidney function.

The table below sets forth representative granted U.S.

patents relating to these and other inventions, including the projected expiration dates of these patents.

DUE TO EXPIRE

Pharmaceuticals and Methods for Treating Hypoxia and Screening Methods Therefor

Stabilization of Hypoxia Inducible Factor (HIF) Alpha

December 2022

Enhanced Erythropoiesis and Iron Metabolism

Compounds and Methods for Treatment of Chemotherapy-Induced Anemia

Methods for Improving Kidney Function

February 2027

In addition to the U.S.

patents listed above, our HIF anemia-related technologies portfolio includes corresponding foreign patents granted and patent applications pending in various territories worldwide.

Akebia and others have filed oppositions against certain European patents within our HIF anemia-related technologies patent portfolio.

In three of these proceedings, for FibroGen European Patent Nos.

1463823, 1633333, and 2322155, the European Patent Office has handed down decisions unfavorable to FibroGen.

In the fourth of these proceedings, the European Patent Office issued a decision favorable to FibroGen, maintaining FibroGen European Patent No.

2322153 in amended form.

All of these decisions are currently under appeal, and these four patents are valid and enforceable pending resolution of the appeals.

The ultimate outcomes of such proceedings remain uncertain, and ultimate resolution of such may take considerable time.

In addition, Akebia has filed oppositions against FibroGen European Patent Nos.

Various legal challenges have been initiated against this portfolio in several territories, including in Europe, the United Kingdom, Canada, and Japan.

Regardless of the final outcome of any such actions, the potential narrowing or revocation of any of these patents does not affect our exclusivity for roxadustat or our freedom-to-operate with respect to use of roxadustat for the treatment of anemia in these or in other territories.

A settlement has been reached in the litigation in Canada, resulting in the discontinuance of the action and leaving FibroGen’s Canadian patents valid and enforceable.

In April 2020, in response to an invalidation action brought against certain of our United Kingdom patents by Akebia, the United Kingdom court handed down a decision invalidating United Kingdom designations of European Patent Nos.

1463823, 1633333, 2298301, 2322153, and 2322155.

Akebia and GSK have also initiated invalidation actions in the United Kingdom against the United Kingdom counterparts of each of these European patents, and GSK has filed for a declaration of non-infringement of certain United Kingdom patents (corresponding to FibroGen European Patent Nos.

2322153 and 2322155) with respect to its daprodustat product.

Akebia is also pursuing invalidation actions against corresponding patents in Canada and in Japan, and invalidation actions against corresponding patents in the United Kingdom have been initiated by GSK and by Akebia, although FibroGen has reached an agreement with GSK that will lead to dismissal of the UK court actions and the proceedings filed by GSK against the patents in the EPO.

Astellas’ proceedings brought against GSK on a quia timet basis have also been dismissed as a result of the settlement agreement.

While we believe the ultimate outcome of all proceedings will be that these FibroGen patents will be upheld in relevant part, we note that narrowing or even revocation of any of these patents would not affect our exclusivity for roxadustat or our freedom-to-operate with respect to use of roxadustat for the treatment of anemia.

The United Kingdom designation to European Patent No.

2289531 was held to be valid in amended form, but not infringed by Akebia.

We and our partner Astellas have filed an appeal of the decision in the United Kingdom Court of Appeal.

Pamrevlumab Patent Portfolio

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We believe that, if pamrevlumab is approved, a full five-year patent term extension under the Hatch-Waxman act will be available for a granted patent relating to pamrevlumab, which extension would expire in 2029 or 2030, depending on the patent extended.

In addition, we believe that pamrevlumab, if approved under a BLA, should qualify for the 12-year period of exclusivity currently permitted by the BPCIA.

Refer to “Government Regulation — Regulatory Exclusivity for Approved Products .”

We also hold additional granted U.S.

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In addition, each sublicense we grant is subject to a one-time fixed amount payment to DFCI.

Unless earlier terminated, the agreement will continue in effect, on a country-by-country basis, until the expiration of all licensed patents in a country or, if there is no patent covering a licensed product incorporating the licensed biological materials, until 20 years after the effective date of the agreement.

The agreement, along with any ongoing payment obligations, will continue in effect until the expiration of all licensed patents on a country-by-country basis, or, if there is no patent covering a licensed product incorporating the licensed biological materials, until 20 years after the effective date of the agreement.

DFCI may terminate the agreement for our uncured material breach, if we cease to carry on our business and development activities with respect to all licensed products, if we fail to comply with our insurance obligations, or if we are convicted of a felony related to the manufacture, use, sale or importation of licensed products.

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We were also obligated to pay an upfront licensing fee of $21,500, all of which has been paid, and development milestone payments of up to $450,000, of which $150,000 has been paid, as well as an additional milestone payment, in the low hundreds of thousands of dollars, for each new indication for which we obtain approval for a licensed product, and a single digit royalty, subject to certain reductions, on net sales of licensed products by us or our affiliates or sublicensees.

Unless earlier terminated, the agreement will continue in effect, on a country-by-country basis, until the expiration of all licensed patents in a country.

The agreement, along with any ongoing payment obligations, will continue in effect until the expiration of all licensed patents, on a country-by-country basis.

The University may terminate the agreement for our uncured material breach or bankruptcy.

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We granted back to Medarex an exclusive, worldwide, royalty-free, perpetual, irrevocable license, with the right to sublicense, to certain inventions created during the parties’ research collaboration, with such license limited to use by Medarex outside the scope of our licensed antibodies.

As a result of the exercise of our option to obtain the commercial license, Medarex is precluded from (i) knowingly using any technology involving immunizable transgenic mice containing unrearranged human immunoglobulin genes with any of our antigen targets that were the subject of the agreement, (ii) granting to a third party a commercial license that covers such antigen targets or those antibodies derived by Medarex during the Research Period, and (iii) using any antibodies derived by Medarex during the Research Period, except as permitted under the agreement for our benefit or to prosecute patent applications in accordance with the agreement.

As a result of the exercise of our option to obtain the commercial license, Medarex is precluded from:

(i) knowingly using any technology involving immunizable transgenic mice containing unrearranged human immunoglobulin genes with any of our antigen targets that were the subject of the agreement,

(ii) granting to a third party a commercial license that covers such antigen targets or those antibodies derived by Medarex during the Research Period, and

(iii) using any antibodies derived by Medarex during the Research Period, except as permitted under the agreement for our benefit or to prosecute patent applications in accordance with the agreement.

Medarex retained ownership of the patent rights relating to certain mice, mice materials, antibodies and hybridoma cell lines used by Medarex in connection with its activities under the agreement, and Medarex also owns certain claims in patents covering inventions that arise during the Research Period, which claims are directed to (i) compositions of matter (e.g., an antibody) except formulations of antibodies for therapeutic or diagnostic use, or (ii) methods of production.

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In addition, during litigation, the patent holder might obtain a preliminary injunction or other equitable right, which could prohibit us from making, using or selling our products, technologies, or methods.

As of January 31, 2020, we had 531 full-time employees, 136 of whom held Ph.D.

degrees, 279 of whom were engaged in research and development and 252 of whom were engaged in manufacturing, sales and marketing, business development, finance, information systems, facilities, human resources or administrative support.

HUMAN RESOURCES

We had a total of 599 employees at FibroGen as of January 31, 2021.

None of our U.S.

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None of our employees have entered into a collective agreement with us.

We consider our employee relations to be good.

We are highly committed to building a diverse, committed, and impassioned team to deliver innovative therapies to patients facing serious unmet medical needs.

In 2020 we developed and approved a new Corporate Vision Statement and Values through the participation and input of many staff across the organization.

One of these core values is “Respect for People” which includes a strong commitment to build a culture of inclusiveness and equality and foster a culture of individual growth and an environment of continued learning.

In 2020, we conducted a company-wide employee engagement survey.

We had an overall participation rate by employees of 86% with over 90% of respondents reporting that they felt engaged around our core values of excellence, respect for people, integrity, and empowerment.

Both of these scores significantly exceed normative industry participation and engagement benchmarks.

The biotechnology industry is an extremely competitive labor market and recruiting and retaining employees is critical to the continued success of our business.

We focus on recruiting, retaining, and developing employees from a diverse range of backgrounds to conduct our research, development, commercialization, and administrative activities.

We consistently review and evaluate our compensation and employee benefits practices to ensure that we recruit and retain a highly trained and diverse workforce.

This includes comprehensive medical and income protection, such as life insurance and retirement savings programs.

In addition to coaching and internal growth and promotion opportunities, we provide employees access to over 5,000 developmental classes and programs through a learning management system.

In 2020 we deployed a state-of-art, human capital management system that will allow us to significantly expand our capabilities to develop and assess our employees.

This system will also allow us to build comprehensive development and succession plans at all levels in the organization to ensure that we have a strong pipeline of highly trained employees.

We also invested in health and safety measures for our employees who must work in the offices and labs during the COVID-19 pandemic.

We are committed to diversity, equity and inclusion.

On our Board of Directors:

five of our twelve members are women and/or from minority racial and ethnic groups.

As of January 31, 2021, women represented 54% of our global workforce and 27% of our global leadership (VP and above).

As of January 31, 2021, 57% of our U.S.

workforce, and 16% of our U.S.

leadership (VP and above), were from minority racial and ethnic groups.

In addition to furthering our investments in our human resources, we plan on continuing our efforts in 2021 in critical environmental, social, and governance areas.

Our corporate and research and development operations are located in San Francisco, California, where we lease approximately 234,000 square feet of office and laboratory space with approximately 35,000 square feet subleased.

The lease for our San Francisco headquarters expires in 2023.

We also lease approximately 67,000 square feet of office and manufacturing space in Beijing, China.

Our lease in China expires in 2021.

We also lease approximately 67,000 square feet of office and manufacturing space in Beijing, China, and multiple office spaces in Beijing and Shanghai, China.

Our leases in China expire in 2023.

We have constructed a commercial manufacturing facility of approximately 5,500 square meters in Cangzhou, China, on approximately 33,000 square meters of land.

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We believe our facilities are adequate for our current needs and that suitable additional or substitute space would be available if needed.

LEGAL PROCEEDINGS

We are not currently a party to any material legal proceedings.

FINANCIAL INFORMATION

Information regarding our revenues, net loss and total assets is contained in our consolidated financial statements under Item 8 of this Annual Report, which information is incorporated by reference here.

For the specifics of our segment and geographic revenue, refer to Note 14 to our consolidated financial statements.

Research and development expenses for fiscal years ended December 31, 2019, 2018 and 2017 were $209.3 million, $235.8 million, and $196.5 million, respectively.

We expect our research and development expenses to continue to increase in the future as we advance our product candidates through clinical trials and expand our product candidate portfolio.

Our revenue to date has been generated primarily from our collaboration agreements with Astellas and AstraZeneca for the development and commercialization of roxadustat.

For fiscal years ended December 31, 2019, 2018 and 2017, substantially all of our revenue was related to our collaboration agreements.

AVAILABLE INFORMATION

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In addition to the information about us and our subsidiaries contained in this Annual Report, information about us can be found on our website.

Our website and information included in or linked to our website are not part of this Annual Report.

Our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), are available free of charge through our website as soon as reasonably practicable after they are electronically filed with or furnished to the Securities and Exchange Commission (“SEC”).

The information contained on, or that can be accessed through, our website is not part of, and is not incorporated into, this Annual Report.

Our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, are available free of charge through our website as soon as reasonably practicable after they are electronically filed with or furnished to the Securities and Exchange Commission (“SEC”).

Additionally the SEC maintains an internet site that contains reports, proxy and information statements and other information.

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CORPORATE INFORMATION

We were incorporated in 1993 in Delaware.

Our headquarters are located at 409 Illinois Street, San Francisco, California 94158 and our telephone number is (415) 978-1200.

Our website address is www.FibroGen.com.

The information contained on, or that can be accessed through, our website is not part of, and is not incorporated into, this Annual Report.

Our subsidiaries consist of the following:

1) FibroGen Europe Oy (“FibroGen Europe”), a majority owned entity incorporated in Finland in 1996;

1) FibroGen Europe Oy, a majority owned entity incorporated in Finland in 1996;

2) Skin Sciences, Inc., a majority owned entity incorporated in the State of Delaware in 1995;

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5) FibroGen International (Hong Kong) Limited, a majority owned entity incorporated in Hong Kong in 2011;

and 6) FibroGen (China) Medical Technology Development Co., Ltd., a majority owned entity incorporated in China in 2011.

6) FibroGen (China) Medical Technology Development Co., Ltd., a majority owned entity incorporated in China in 2011;

and 7) Beijing Falikang Pharmaceutical Co.

Ltd., an unconsolidated variable interest entity incorporated in China in 2020.

“FibroGen,” the FibroGen logo and other trademarks or service marks of FibroGen, Inc.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business