Treatments for Anemia in Chronic Kidney Disease: Effectiveness and Value Report Supplement January 28, 2021 Prepared for ©Institute for Clinical and Economic Review, 2021 Table of Contents A. Background: Supplemental Information ........................................................................................... 1 A1. Definitions .................................................................................................................................... 1 A2. Potential Cost-Saving Measures .................................................................................................. 1 B. Patient Perspectives: Supplemental Information .............................................................................. 3 B1. Methods ....................................................................................................................................... 3 C. Clinical Guidelines .............................................................................................................................. 4 D. Comparative Clinical Effectiveness: Supplemental Information ....................................................... 5 D1. Detailed Methods ........................................................................................................................ 5 D2. Supplemental Results ................................................................................................................ 13 D3. Evidence Tables ......................................................................................................................... 46 D4. Heterogeneity and Subgroups ................................................................................................. 113 D5. Ongoing Studies ....................................................................................................................... 115 D6. Previous Systematic Reviews and Technology Assessments .................................................. 120 E. Long-Term Cost-Effectiveness: Supplemental Information ........................................................... 123 E1. Detailed Methods..................................................................................................................... 123 E2. Model Inputs and Assumptions ............................................................................................... 125 E3. Results ...................................................................................................................................... 134 E4. Sensitivity Analyses .................................................................................................................. 135 E5. Scenario Analyses ..................................................................................................................... 138 E6. Heterogeneity and Subgroups ................................................................................................. 140 E7. Model Validation ...................................................................................................................... 140 F. Potential Other Benefits and Contextual Considerations .............................................................. 142 G. Potential Budget Impact: Supplemental Information ................................................................... 144 Methods ......................................................................................................................................... 144 References ......................................................................................................................................... 145 Evidence Table References ................................................................................................................ 153 ©Institute for Clinical and Economic Review, 2021 List of Acronyms and Abbreviations Used in the Report Supplement AE Adverse event AMCP Academy of Managed Care Pharmacy CFB Change from baseline CI Confidence interval CRP C-reactive protein CKD Chronic kidney disease DD Dialysis dependent DI Dialysis independent ESA Erythropoiesis-stimulating agent ESKD End-stage kidney disease ESRD End-stage renal disease evLYG Equal value life years gained FDA Food and Drug Administration g/dL Grams per deciliter GFR Glomerular filtration rate Hb Hemoglobin HD Hemodialysis HDL High-density lipoprotein HIF-PH Hypoxia-inducible factor prolyl hydroxylase HR Hazard ratio HRQoL Health-related quality of life ID Incident dialysis ITT Intention-to-treat IV Intravenous KDIGO Kidney Disease Improving Global Outcomes KDOQI Kidney Disease Outcomes Quality Initiative LDL Low-density lipoprotein LSM Least squares mean LY Life year MA Meta-analysis MACE Major adverse cardiovascular event MCID Minimum clinically important difference MD Mean difference MI Myocardial infarction NICE National Institute for Health and Care Excellence NKF National Kidney Foundation NYHA New York Heart Association PD Peritoneal dialysis PICOTS Population, Intervention, Comparators, Outcomes, Timing, and Settings Framework PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses QALY Quality-adjusted life year RBC Red blood cell RCT Randomized controlled trial RR Risk ratio SF-36 (PF/VT) Short Form 36 Health Survey (Physical Functioning/Vitality) TEAE Treatment-emergent adverse event TSAT Transferrin saturation USPSTF United States Preventive Services Task Force WHO World Health Organization WAC Wholesale acquisition cost ©Institute for Clinical and Economic Review, 2021 Page ii Report Supplement – Treatments for Anemia in CKD Return to Table of Contents A. Background: Supplemental Information A1. Definitions Anemia is defined as “a condition in which the number of red blood cells or their oxygen-carrying capacity is insufficient to meet physiological needs.”1 In anemia, insufficient numbers of circulating red blood cells or inadequate quantities of iron or functional hemoglobin (Hb) are available to transport and release oxygen to tissues. The World Health Organization (WHO) and the 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines define anemia as a Hb level of <12 g/dL in females and <13 g/dL in adult males. However, this definition does not provide goals of treatment for different patients’ groups.2,3 Chronic kidney disease (CKD) is a condition characterized by a gradual loss of kidney function over time. The definition and classification of CKD guidelines were established and endorsed by the National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) and the international KDIGO guideline group.4-7 CKD is defined by the presence of kidney damage or decreased kidney function for three or more months.8 Decreased kidney function refers to a decreased in glomerular filtration rate (GFR), which is usually estimated (eGFR) using serum creatinine and one of several available equations.9-11 Patients who are diagnosed with CKD can be categorized into different stages according to the cause, their GFR (six G-stages; G-I: ≥90 ml/min per 1.73 m2, G-II: 60-89, G-IIIa: 45-59, G-IIIb: 30-44, G-IV: 15-29, G-V: <15 ml/min per 1.73 m2), and the amount of albumin or protein in the urine (three A-stages; A-1: <30, A-2: 30-299, and A-3: ≤300 mg/g). Additionally, patients with CKD can advance from being dialysis independent (DI-CKD) to renal failure (also known as end-stage kidney disease [ESKD]), which is defined as severely reduced kidney function or treatment with dialysis (dialysis dependent [DD-CKD]) or transplantation. Risk factors for CKD include genetic or sociodemographic predisposition, or the presence of diseases that can initiate and propagate kidney disease. A2. Potential Cost-Saving Measures ICER includes in its reports information on wasteful or lower-value services in the same clinical area that could be reduced or eliminated to create headroom in health care budgets for higher-value innovative services (for more information, see https://icer.org/our-approach/methods- process/value-assessment-framework/). These services are ones that would not be directly affected by roxadustat (e.g., reduction in blood transfusion), as these services will be captured in the economic model. Rather, we are seeking services used in the current management of CKD beyond the potential offsets that arise from a new intervention. During stakeholder engagement and public comment periods, ICER encouraged all stakeholders to suggest services (including ©Institute for Clinical and Economic Review, 2021 Page 1 Report Supplement – Treatments for Anemia in CKD Return to Table of Contents treatments and mechanisms of care) currently used for patients with CKD that could be reduced, eliminated, or made more efficient. No suggestions were received. ©Institute for Clinical and Economic Review, 2021 Page 2 Report Supplement – Treatments for Anemia in CKD Return to Table of Contents B. Patient Perspectives: Supplemental Information B1. Methods ICER engaged with patients with CKD (DI-CKD, DD-CKD, and post-transplant), caregivers, representatives from professional and advocacy organizations, and clinical experts to understand the specific challenges associated with ongoing management of anemia in CKD from the patient perspective. ICER engaged with these groups using different platforms including webinars, one-on- one meetings, group meetings, and written communication. ©Institute for Clinical and Economic Review, 2021 Page 3 Report Supplement – Treatments for Anemia in CKD Return to Table of Contents C. Clinical Guidelines Multiple