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Roxadustat for the Treatment of Anemia Due to Chronic Kidney

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Roxadustat for the Treatment of Anemia Due to Chronic Kidney Roxadustat for the Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients not on Dialysis and on Dialysis FDA Presentation Cardiovascular and Renal Drugs Advisory Committee Meeting July 15, 2021 Clinical: Saleh Ayache, MD Division of Non-Malignant Hematology Office of Cardiology, Hematology, Endocrinology, and Nephrology Statistics: Jae Joon Song, PhD Division of Biometrics VII/Office of Biostatistics www.fda.gov Roxadustat Review Team • Clinical • Quality Assessment • Biopharmaceutics Saleh Ayache Ben Zhang Joan Zhao Ann T. Farrell Dan Berger • Labeling Nancy Waites Ellis Unger Virginia Kwitkowski • Clinical Pharmacology • Project Management • Clinical Outcome Assessment Snehal Samant Alexis Childers Naomi Knoble Jihye Ahn Courtney Hamilton • Division of Hepatology and Nutrition Sudharshan Hariharan Paul H. Hayashi • Pharmacology Toxicology Doanh Tran Mark Avigan Geeta Negi • Statistics • Office of Scientific Investigations Todd Bourcier Lola Luo Anthony Orencia Jae Joon Song Clara Kim Yeh-Fong Chen Thomas Gwise Mat Soukup www.fda.gov 2 Outline of Presentation • Product and proposed indication • Regulatory history and background • Roxadustat development program • Efficacy Safety • Adverse events • Major adverse cardiovascular events • All-cause mortality • Exploratory analyses of the relationships between thromboembolic events, drug dose, hemoglobin, and rate of change of hemoglobin www.fda.gov 3 Product and Proposed Indication • Roxadustat: small-molecule, oral, hypoxia inducible- factor prolyl-hydroxylase inhibitor (HIF-PHI), posited to enhance erythropoiesis by increasing endogenous erythropoietin (EPO) and reducing hepcidin • First in its class • Proposed indication: For the treatment of anemia due to chronic kidney disease (CKD) in adult patients not on dialysis and on dialysis • Orally administered • Dose adjusted on basis of hemoglobin response www.fda.gov 4 Marketing Status • Not approved in the United States • Approved in People’s Republic of China 2018 • Approved in Japan 2019 www.fda.gov 5 Anemia in Patients with Chronic Kidney Disease (CKD) • Associated with increased cardiovascular morbidity and mortality • Etiology of anemia is multifactorial: – EPO deficiency – Impaired ability to absorb iron (iron deficiency) and inability to utilize stored iron (chronic disease) – Blood loss – Shortened red blood cell (RBC) survival • Current standard of care: – Iron supplementation (oral or intravenous) – Erythropoiesis-stimulating agents (ESAs) – RBC transfusion www.fda.gov 6 Erythropoietin Stimulating Agents (ESAs) • Erythropoiesis stimulating glycoproteins produced by recombinant DNA technology – Epoetin alfa (Epogen/Procrit), 1989 – Darbepoetin alfa (Aranesp), 2001 – Methoxy polyethylene glycol-epoetin beta (Mircera), 2007 – Epoetin alfa-epbx (Retacrit), biosimilar to epoetin alfa, 2018 • Approved for the treatment of anemia due to CKD in patients on dialysis (dialysis-dependent [DD]) and not on dialysis (non-dialysis­ dependent [NDD]) • Administered intravenously or subcutaneously—none are oral www.fda.gov 7 Hemoglobin “Target” Studies Have Shaped ESA Labeling • Four large, randomized, controlled trials: – Normal hematocrit study – Correction of hemoglobin outcomes in renal insufficiency (CHOIR) – Cardiovascular risk reduction by early anemia treatment with epoetin-beta (CREATE) study – Trial to reduce cardiovascular events with Aranesp therapy (TREAT) • All showed (or tended to show) adverse cardiovascular outcomes with higher rather than lower hemoglobin targets • 30+ years after approval of the first ESA, the optimum hemoglobin target remains unknown www.fda.gov 8 ESA Boxed Warning WARNING: ESAs increase the risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access…. • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin > 11 g/dL. • No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. • Use the lowest dose sufficient to reduce the need for RBC transfusions. www.fda.gov 9 ESA Warnings and Precautions • Increased mortality, myocardial infarction, stroke, and thromboembolism: Using ESAs to target a hemoglobin level > 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit. • Hypertension: Control hypertension prior to initiating and during treatment. • Seizures: ESAs increase seizure risk. www.fda.gov 10 Advisory Committee Meeting Following TREAT • October 2010 – Cardiovascular and Renal Drugs Advisory Committee Meeting Question # 1: …should the indication for darbepoetin alfa for…patients not on dialysis be withdrawn? – Yes: 1 – No: 15 – Abstain: 1 www.fda.gov 11 Roxadustat Development Program • Concurrent development programs for anemia of CKD: – Patients not on dialysis (NDD) – Patients on dialysis (DD) – Three main trials for each patient population, plus one additional trial • Efficacy and safety analyses – Efficacy: • Demonstration of an increase in hemoglobin – Safety: • Major adverse cardiovascular events (MACE): – comparison to placebo in NDD population – comparison to epoetin alfa in DD population • General safety assessment: adverse events, laboratory data, vital signs www.fda.gov 12 Phase 3 Studies—Non-dialysis-dependent (NDD) Population Hemoglobin Study Location Design Randomization/n 1° Endpoint Baseline/Target 1:1 001 Global roxadustat 1384 Randomized, double- placebo 1377 Baseline ≤ 10.0 blind, placebo-controlled 2:1 Hemoglobin averaged over g/dL Weeks 28-52, ∆ from 060 Global studies; roxadustat 616 patients with stage 3-5 Target 11.0 ± 1.0 baseline, regardless of CKD and anemia placebo 306 g/dL rescue therapy 2:1 608 Global roxadustat 391 placebo 203 Randomized, open-label, Percentage of hemoglobin 1:1 Baseline ≤ 10.0 active-controlled study; (Hb) responders (Hb ≥ 11.0 g/dL 610 Europe patients with stage 3-5 roxadustat 323 g/dL and ≥ 1.0 g/dL from Target 11.0 ± 1.0 CKD and anemia baseline) during the first 24 darbepoetin alfa 293 g/dL weeks www.fda.gov 13 Phase 3 Studies—Dialysis-dependent (DD) Population Hemoglobin Study Location Design Randomization/n 1° Endpoint Baseline/Target 1:1 ESA naïve 002 Global roxadustat 1051 Baseline ≤ 10.0 Randomized, open-label, epoetin alfa 1055 g/dL active-controlled studies; 1:1 ESA not naïve Hemoglobin 063 Global patients on dialysis and roxadustat 522 Baseline ≥ 9.0 ­ averaged over weeks anemia epoetin alfa 521 ≤12.0 g/dL 28-52, 1:1 ∆ from baseline, roxadustat 370 Target 11.0 ± 1.0 064 U.S regardless of rescue g/dL epoetin alfa 371 therapy Randomized, open-label, ≥ 9.5 - ≤12.0 g/dL 1:1 active-controlled study; 613 Europe roxadustat 414 patients on stable dialysis Target 11.0 ± 1.0 ESA* 420 and anemia g/dL *epoetin alfa or darbepoetin alfa www.fda.gov 14 Roxadustat Efficacy • The FDA corroborated the Applicant’s efficacy results with respect to hemoglobin. • FDA believes that the Applicant has provided substantial evidence of efficacy for roxadustat. • Our major efficacy concern is hemoglobin overcorrection/ overshoot. www.fda.gov 15 1° Endpoint: Change in Hemoglobin (NDD Studies) 12 12 11 11 ∆ ∆ = 1.69 g/dL 10 = 1.85 g/dL 10 Hb* (g/dL) 9 Hb* (g/dL) 9 Study 060 Study 608 8 8 0 24 52 0 24 52 Time (weeks) Time (weeks) 12 11 — Roxadustat 10 ∆ = 1.35 g/dL — Placebo Hb* (g/dL) 9 8 Study 001 0 24 52 Time (weeks) *Hb = hemoglobin www.fda.gov 16 Secondary Endpoint: Time-to-RBC Transfusions (NDD Studies) • Study 001: statistically significant treatment effect; hazard ratio 0.37, p < 0.05 • Study 060: nominally statistically significant treatment effect; lack of statistical significance for an endpoint more proximal in the testing sequence • Study 608: this endpoint was not included in the testing sequence. An exploratory analysis indicated a nominally statistically significant treatment effect. www.fda.gov 17 Percent of Subjects with RBC Transfusions (NDD Studies) (Exploratory Endpoint) % with RBC Transfusion RBC with % 12.7 23.3 5.6 15.4 8.5 19.2 www.fda.gov 18 Efficacy Endpoint: Study 610 (Hemoglobin Response Rate) Primary endpoint: % hemoglobin responders during the first 24 weeks of treatment. • Note that hemoglobin increases more rapidly in the roxadustat group before 4 weeks Roxadustat Darbepoetin alfa Roxadustat N=286 N=272 12 Number (%) 256 (89.5%) 213 (78.0%) responders 11 95% Confidence (85.4%, 92.8%) (72.6%, 82.8%) Darbepoetin alfa Interval (CI) Hb (g/dL) 10 Difference of proportions 11.5% 9 (roxadustat – 0 1 2 4 8 12 16 20 darbepoetin) Time (Weeks) 95% CI of (5.7%, 17.4%) difference www.fda.gov 19 Hemoglobin Change Over Time (DD Studies) 12 11 11 ∆ = 0.18 g/dL 10 10 ∆ = 0.48 g/dL 9 (g/dL)Hb Hb (g/dL) Study 063 9 Study 064 8 8 0 24 52 0 24 52 Time (weeks) Time (weeks) 12 — Roxadustat 11 ∆ = 0.09 g/dL 10 — Epoetin alfa Hb (g/dL)Hb 9 Study 002 8 Test of non-inferiority for difference in 0 24 52 hemoglobin between groups Time (weeks) (- 0.75 g/dL) was met for all studies www.fda.gov 20 Primary Endpoint: Study 613 (Change in Hemoglobin) 1° endpoint: ∆ in hemoglobin from baseline to mean during Weeks 28 to 52 Non-inferiority margin met for difference between groups (- 0.75 g/dL) Roxadustat ESA (N=415) (N=421) Mean (SD) baseline Hb, 10.75 (0.62) 10.78 (0.62) g/dL 12.0 Mean (SD) week 28-52 11.15 (0.62) 10.96 (0.66) Hb, g/dL 11.5 Roxadustat Least Squares mean 0.36 0.19 (LSM) (roxadustat– (0.29, 0.44) (0.12, 0.26) ESA), g/dL (95% CI) Hb (g/dL) 11.0 LSM Difference 0.17
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