Vadadustat

VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. Limitations of Use VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being. VAFSEO is not indicated for use: As a substitute for red blood cell transfusions in patients who require immediate correction of anemia In patients with anemia due to CKD not on dialysis [see Warnings and Precautions ( 5.6 )] . VAFSEO is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months. ( 1 ) Limitations of Use Not been shown to improve quality of life, fatigue, or patient well-being. Not indicated for use: As a substitute for transfusion in patients requiring immediate correction of anemia. ( 1 ) In patients with anemia due to CKD not on dialysis. ( 1 , 5.6 )

VAFSEO is available as a film-coated, immediate-release tablet in the following strengths: Tablet Strength Tablet Shape/Color Tablet Markings 150 mg round/white “VDT” and “150” 300 mg oval/yellow “VDT” and “300” 450 mg oval/pink “VDT” and “450” Tablets: 150 mg, 300 mg and 450 mg ( 3 )

VAFSEO is contraindicated in patients: with a known hypersensitivity to VAFSEO or any of its components [see Description ( 11 )] . with uncontrolled hypertension [see Warnings and Precautions ( 5.3 )] . Known hypersensitivity to VAFSEO or any of its components ( 4 ) Uncontrolled hypertension ( 4 )

Hepatotoxicity: Has been reported in patients taking VAFSEO. Measure ALT, AST and bilirubin prior to the initiation of VAFSEO, monthly after initiation for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. ( 5.2 ) Hypertension: Worsening hypertension, including hypertensive crisis may occur. Monitor blood pressure. Adjust anti-hypertensive therapy as needed. ( 5.3 ) Seizures: Seizures have occurred in patients with CKD taking VAFSEO. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency. ( 5.4 ) Gastrointestinal Erosion: Gastric or esophageal erosions and gastrointestinal bleeding have been reported. ( 5.5 ) Malignancy: May have unfavorable effects on cancer growth. Not recommended if active malignancy. ( 5.7 )

5.1 Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access VAFSEO increases the risk of arterial and venous thrombotic events, that may be fatal, including myocardial infarction, stroke, venous thromboembolism and vascular access thrombosis [see Boxed Warning , Adverse Reactions ( 6.1 )] . Patients with cardiovascular or cerebrovascular disease are at increased risk of these events. Avoid use in patients with a history of myocardial infarction, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting VAFSEO. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks. Targeting a hemoglobin level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with ESAs, which also increase erythropoietin levels. No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks. Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions. Adherence to dosing and hemoglobin monitoring recommendations is important to avoid excessive erythropoiesis [see Dosage and Administration ( 2.4 )] . Advise patients to seek immediate medical attention if they develop signs or symptoms of myocardial infarction, stroke, venous thromboembolism, or thrombosis of vascular access. Evaluate and manage promptly if these occur.

5.2 Hepatotoxicity VAFSEO may cause hepatotoxicity. In clinical trials, hepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one case of severe hepatocellular injury with jaundice. All events were asymptomatic and resolved after discontinuation of VAFSEO. The time to onset was generally within the first 3 months of treatment. Elevated serum ALT, AST, and bilirubin were seen in 1.8%, 1.8% and 0.3% of CKD patients treated with VAFSEO, respectively. Measure ALT, AST and bilirubin prior to the initiation of VAFSEO and monthly after initiation for the first 6 months and then monitor as clinically indicated [see Dosage and Administration ( 2.1 )] . Discontinue VAFSEO if there is persistent ALT or AST greater than 3 times ULN or if ALT or AST elevations greater than 3 times upper limit of normal (ULN) are accompanied by a bilirubin increase greater than 2 times ULN. VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease.

5.3 Hypertension VAFSEO is contraindicated in patients with uncontrolled hypertension. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, worsening of hypertension was reported in 14% (9.4 per 100 person-years [PY]) of patients receiving VAFSEO and 17% (11.8 per 100 PY) of patients receiving darbepoetin alfa. Serious worsening of hypertension was reported in 2.7% (1.7 per 100 PY) of patients receiving VAFSEO and 3% (1.8 per 100 PY) of patients receiving darbepoetin alfa. Cases of hypertensive crisis including hypertensive encephalopathy and seizures have also been reported in patients receiving VAFSEO. Periodically monitor blood pressure and adjust or initiate anti-hypertensive therapy as needed.

5.4 Seizures Seizures have occurred in patients treated with VAFSEO. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, seizures occurred in 1.6% (1.0 per 100 PY) of patients who received VAFSEO and 1.6% (1.0 per 100 PY) of patients who received darbepoetin alfa. Following initiation of VAFSEO, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms, or change in seizure frequency.

5.5 Gastrointestinal Erosion In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, gastric or esophageal erosions occurred in 6.4% (4.0 per 100 PY) of patients receiving VAFSEO and 5.3% (3.3 per 100 PY) of darbepoetin alfa-treated patients. Serious gastrointestinal erosions, including gastrointestinal bleeding and the need for red blood cell transfusions were reported in 3.4% (2.1 per 100 PY) and 3.3% (2.0 per 100 PY) of those receiving VAFSEO and darbepoetin alfa, respectively. Consider this risk particularly in patients at increased risk for gastrointestinal erosions, such as those with a history of gastrointestinal erosion, peptic ulcer disease, use of concomitant medications that increase the risk of gastrointestinal erosion, and current tobacco smokers and alcohol drinkers. Advise patients of the symptoms and signs of gastric and esophageal erosions and of gastrointestinal bleeding and to seek prompt medical care if these occur.

5.6 Serious Adverse Reactions in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis The safety of VAFSEO has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting [see Indications and Usage ( 1 )] . In large clinical trials in adults with anemia of CKD who were not on dialysis (PRO 2 TECT-1 and PRO 2 TECT-2), an increased risk of mortality, stroke, myocardial infarction, serious acute kidney injury, serious hepatic injury, and serious gastrointestinal erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa.

5.7 Malignancy Because increased hypoxia inducible factor (HIF)-1 levels may be associated with unfavorable effects on cancer growth, VAFSEO has not been studied and is not recommended in patients with active malignancies. In the INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials, malignancies were observed in 2.2% (1.3 per 100 PY) of patients treated with VAFSEO and 3.0% (1.8 per 100 PY) of patients treated with darbepoetin alfa. No evidence of increased carcinogenicity was observed in animal studies [see Nonclinical Toxicology ( 13.1 )] .

The following clinically significant adverse reactions are discussed elsewhere in the labeling: Increased risk of death, myocardial infarction, stroke, venous thromboembolism, and thrombosis of vascular access [see Boxed Warning and Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] Seizures [see Warnings and Precautions ( 5.4 )] Gastrointestinal erosion [see Warnings and Precautions ( 5.5 )] Serious adverse reactions in patients with anemia due to chronic kidney disease and not on dialysis [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Akebia Therapeutics, Inc. at 1-844-445-3799 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VAFSEO was evaluated in adults with dialysis-dependent chronic kidney disease (DD-CKD) with anemia in the INNO 2 VATE-1 and INNO 2 VATE-2 trials [see Clinical Studies ( 14.1 )] . Both trials randomized patients to VAFSEO or darbepoetin alfa. Results in this section are based on the pooled VAFSEO treatment arms and pooled darbepoetin alfa arms from these trials. There were 1947 patients treated with VAFSEO and 1955 patients treated with darbepoetin alfa. In the pooled VAFSEO treatment arm, 71% of the participants were treated continuously for at least 6 months of VAFSEO and 44% of participants received VAFSEO for at least 1 year. VAFSEO was non-inferior to darbepoetin alfa on the time to first occurrence of major adverse cardiovascular events (MACE) in adults with anemia due to CKD who were on dialysis [see Clinical Studies ( 14.1 )] . Permanent treatment discontinuation due to an adverse reaction was reported in 4.9% of patients treated with VAFSEO and 1.1% of patients treated with darbepoetin alfa. Gastrointestinal symptoms (nausea, vomiting and diarrhea) resulted in permanent treatment discontinuation in 1.8% of patients treated with VAFSEO. The most common adverse reactions (>10% of VAFSEO-treated patients) were hypertension and diarrhea. Table 1 lists the adverse reactions that occurred in at least 5% or greater of patients with DD-CKD treated with VAFSEO. Table 1 Adverse Reactions (≥5%) in Patients with DD-CKD During INNO 2 VATE-1 and INNO 2 VATE-2 * Grouped Terms Hypertension includes hypertensive crisis, pre-eclampsia and hypertensive encephalopathy. Headache includes occipital neuralgia. Fatigue includes asthenia, lethargy and malaise. Vomiting includes hematemesis. Gastrointestinal erosion includes duodenal ulcers and perforation, gastrointestinal ulcers and perforation, esophageal ulcers and perforation, and unspecified site or hematemesis, gastrointestinal hemorrhage, helicobacter duodenitis and gastritis, melaena, and gastric hemorrhage. Dizziness includes labyrinthitis, vertigo, vestibular neuronitis and presyncope. Dyspnea includes orthopnea and respiratory distress. Adverse Reactions VAFSEO N=1947 (%) Darbepoetin Alfa N=1955 (%) Hypertension * 14 17 Diarrhea 13 10 Headache * 9 8 Nausea 8 8 Fatigue * 8 5 Abdominal pain 7 7 Vomiting * 7 7 Gastrointestinal erosion * 6 5 Dizziness * 6 5 Dyspnea * 6 7 Arteriovenous fistula thrombosis 6 5 Dialysis related complication 5 7 Adjudicated fatal and non-fatal thrombotic vascular events were observed in 9.0 per 100 PY of patients in the pooled VAFSEO arm and in 8.7 per 100 PY of patients in the pooled darbepoetin alfa (see Table 2) . Table 2 Adjudicated Thrombotic Vascular Events in Patients with DD-CKD (Fatal and Non-fatal Events) * PY = Person Years * These data are not an adequate basis for comparison of rates between the study drug and active control. ** Based on time to first event analysis. Event VAFSEO (N = 1947) Darbepoetin Alfa (N = 1955) Rate per 100 PY ** Rate per 100 PY ** Vascular access thrombosis 4.8

3.9 Myocardial infarction 2.9

2.8 Stroke 1.1

1.4 Deep vein thrombosis 0.5

0.6 Pulmonary embolism 0.2

0.3 Arterial thrombosis 0.2 0.1

Iron supplements and iron-containing phosphate binders: Administer VAFSEO at least 1 hour before products containing iron. ( 7.1 ) Non-iron-containing phosphate binders: Administer VAFSEO at least 1 hour before or 2 hours after non-iron-containing phosphate binders. ( 7.1 ) BCRP substrates: Monitor for signs of substrate adverse reactions and consider substrate dose reduction. ( 7.2 ) Statins: Monitor for statin-related adverse reactions ( 7.2 ).

7.1 Effect of Other Drugs on VAFSEO Table 3 describes clinically significant drug interactions where concomitant use of another drug affects VAFSEO. Table 3 Drug Interactions with VAFSEO that Affect Vadadustat Exposure Iron supplements and phosphate binders Clinical Effect Co-administration with oral iron supplements, products containing iron, or phosphate binders decreases the exposure of vadadustat [ see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of VAFSEO. Prevention or Management Stagger administration when VAFSEO is used with oral iron supplements, products containing iron, iron-containing phosphate binders, or non-iron-containing phosphate binders [see Dosage and Administration ( 2.5 )] . Examples * Iron supplements : ferric citrate, ferrous sulfate, sodium ferrous citrate Iron-containing phosphate binders : ferric citrate, sucroferric oxyhydroxide Non-iron-containing phosphate binders : calcium acetate, sevelamer carbonate Organic anion transporter (OAT) OAT1/OAT3 inhibitors Clinical Effect Co-administration with OAT1/OAT3 (Organic Anion Transporter) inhibitors may increase the area under the concentration curve (AUC) of vadadustat [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of VAFSEO adverse reactions. Prevention or Management Closely monitor for too large or too rapid an increase in Hb response and for adverse reactions. Examples * OAT1 inhibitors: probenecid, rifampicin OAT3 inhibitors: gemfibrozil, probenecid, teriflunomide * These examples are not a comprehensive list of all possible drugs that may fit this category.

7.2 Effect of VAFSEO on Other Drugs Table 4 describes clinically significant drug interactions where VAFSEO affects the co-administered drug. Table 4 Drug Interactions with VAFSEO that affect co-administered drugs BCRP substrates Clinical Effect Vadadustat may increase the exposure of BCRP substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to the BCRP substrate. Prevention or Management Monitor for signs of adverse effects of the co-administered BCRP substrate and reduce substrates’ dosage in accordance with their approved product labeling, if needed. Example * sulfasalazine Statins Clinical Effect Vadadustat increases the maximal concentration (C max ) and AUC of some statins when co-administered [see Clinical Pharmacology ( 12.3 )] . Prevention or Management Monitor for possible statin-related adverse reactions. Concomitant Drug Name Recommendation Simvastatin Starting dose of simvastatin should be 5 mg/day. Maximum daily dose of simvastatin not to exceed 20 mg. Rosuvastatin Maximum daily dose of rosuvastatin not to exceed 5 mg. OAT3 substrates Clinical Effect Vadadustat may increase the exposure of co-administered OAT3 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Prevention or Management Monitor for signs of adverse reactions of the co-administered OAT3 substrates and adjust substrates’ dosage in accordance with their approved product labeling, if needed. Examples * cefaclor, ceftizoxime, famotidine, furosemide, oseltamivir carboxylate, penicillin G, sitagliptin * These examples are not a comprehensive list of all possible drugs that may fit this category.

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Breastfeeding not recommended until two days after the final dose. ( 8.2 ) Hepatic Impairment: Not recommended for use in patients with cirrhosis or active, acute liver disease. ( 8.6 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to VAFSEO during pregnancy. Health care providers and patients are encouraged to report pregnancies by calling 1-844-445-3799. Risk Summary Available data with VAFSEO use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with CKD (see Clinical Considerations) . Vadadustat administration orally to pregnant rats and rabbits during the period of organogenesis was associated with reduced fetal weight at doses that caused maternal toxicity. In rat and rabbit studies, vadadustat was not teratogenic (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. VAFSEO should only be used during pregnancy if the benefit justifies the potential risk to the fetus. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: CKD in pregnancy increases the risk for maternal hypertension, preeclampsia, miscarriage, stillbirth, preterm delivery, low birth weight infants, and polyhydramnios. Data Animal Data Vadadustat decreased fetal weight and reduced fetal skeletal ossification in rats at a dose of 160 mg/kg/day (1.7 times the maximum recommended human dose [MRHD] based on AUC), which was associated with maternal toxicity defined by reduced body weight gain and food consumption. Vadadustat was orally administered to pregnant rabbits at doses of 10, 25, or 50 mg/kg/day from gestation day 6 until gestation day 18 during the period of organogenesis. Vadadustat administration at 50 mg/kg/day resulted in maternal toxicity of reduced body weight gain, but no adverse effects on embryofetal development were observed at doses less than or equal to 50 mg/kg/day (1.5 times the MRHD based on AUC). In a pre- and postnatal development study, pregnant rats were dosed orally with vadadustat 20, 40, or 80 mg/kg/day from implantation until weaning (gestation day 6 to lactation day 20) at 20, 40, or 80 mg/kg/day. There were decreased body weights of offspring at the dose of 80 mg/kg/day but no adverse effects were observed at doses less than or equal to 80 mg/kg/day (0.3 times the MRHD based on AUC) in dams.

8.2 Lactation Risk Summary There are no data on the presence of vadadustat in human milk, the effects of vadadustat on the breastfed child, or the effects on milk production. Vadadustat is present in the milk of lactating rats (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in adults treated with VAFSEO, such as thrombotic vascular events, advise patients not to breastfeed during treatment with VAFSEO, and for 2 days after the final dose. Data Vadadustat was detected in the milk of lactating rats after a single oral administration of radiolabeled vadadustat at 50 mg/kg. The maximum ratio of milk to plasma concentration in rats was 14.5 at 8 hours postdose and the ratio of milk to plasma AUC was 6.

8.4 Pediatric Use The safety and effectiveness of VAFSEO in pediatric patients have not been established.

8.5 Geriatric Use There were 1330 patients 65 years of age and older in the pooled INNO 2 VATE-1 and INNO 2 VATE-2 clinical trials. Of the total number of VAFSEO-treated patients in these studies, 449 (23%) were 65 to 74 years of age, 194 (10%) were 75 to 84 years of age, and 24 (1%) were 85 years of age and older. No overall differences in safety or effectiveness were observed between patients 65 years of age and older and younger adult patients [see Clinical Studies ( 14.1 )] .

8.6 Hepatic Impairment VAFSEO is not recommended in patients with cirrhosis or active, acute liver disease [see Warnings and Precautions ( 5.2 )] .

Vadadustat is a reversible inhibitor of HIF-prolyl-4-hydroxylases (PH)1, PH2, and PH3 (IC 50 in the nM range). This activity results in the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors, and increased production of erythropoietin (EPO).