The Emerging Picture of Anemia in Chronic Kidney Disease by Integritas Communications

ANEMIA OF CKD PATHOPHYSIOLOGY

What Contributes to Anemia of CKD? Chronic Kidney Disease1-3

Altered EPO Production

Inflammation

Hepcidin Secretion

Functional Iron Deficiency CKD, chronic kidney disease; EPO, erythropoietin. 1. Koury MJ, Haase VH. Nat Rev Nephrol. 2015;11(7):394-410. 2. Babbitt JL, Lin HY. J Am Soc Nephrol. 2012;23(10):1631-1634. 3. Spinowitz B, et al. J Med Econ. 2019;22(6):593-604.

Anemia of CKD Chronic Kidney Disease1-3

Altered EPO Production

Inflammation

Hepcidin Secretion

Functional Iron Deficiency 1. Koury MJ, Haase VH. Nat Rev Nephrol. 2015;11(7):394-410. 2. Babbitt JL, Lin HY. J Am Soc Nephrol. 2012;23(10):1631-1634. 3. Spinowitz B, et al. J Med Econ. 2019;22(6):593-604.

Anemia of CKD Chronic Kidney Disease1-3

Altered EPO Production

Inflammation

Hepcidin Secretion

Anemia of CKD Chronic Kidney Disease1-3

Altered EPO Production

Inflammation

Hepcidin Secretion

Other Potential Causes of Anemia in Patients Who Have CKD

• Absolute iron deficiency • Inflammation, causing inadequate bone marrow response to EPO • Attenuated RBC survival • Secondary hyperparathyroidism

RBC, red blood cell. Geddes CC. Nephrol Dial Transplant. 2019;34(6):921-922.

PREVALENCE AND BURDEN

Prevalence â&#x20AC;˘ CKD affects approximately 37 million American adults1 â&#x20AC;˘ Prevalence of anemia increases with severity of CKD2 60

Prevalence. %

40 30

20 10 0

8.4 Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

1. Centers for Disease Control and Prevention (CDC). Chronic kidney disease in the United States, 2019. www.cdc.gov/kidneydisease/publications-resources/2019national-facts.html. Accessed May 14, 2020. 2. Stauffer ME, Fan T. PloS One. 2014;9(1):e84943.

KDIGO Definition of Anemia of CKD • Anemia of CKD is caused by insufficient erythropoiesis • Anemia in adults and teenagers aged >15 years with CKD is diagnosed when the Hb concentration is1 – <13.0 g/dL in men – <12.0 g/dL in women

• KDIGO: To identify anemia in people with CKD, measure Hb concentration when clinically indicated and1 – At least annually in patients with stage 3 CKD – At least twice per year in patients with stage 4 or 5 NDD-CKD – At least every 3 months in patients with peritoneal dialysis or DD-CKD (stage 5)

DD-CKD, dialysis-dependent (stage 5) chronic kidney disease; Hb, hemoglobin; KDIGO, Kidney Disease Improving Global Outcomes; NDD-CKD, nondialysis-dependent CKD. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. Kidney Int Suppl. 2013;1:279-335.

Manifestations of Anemia of CKD â&#x20AC;˘ Malaise, fatigue, weakness, dyspnea, impaired cognition, and other symptoms

Improving anemia improves cognitive function, sexual function, general well-being, and exercise capacity and reduces the need for blood transfusions. Mehdi U, Toto RD. Diabetes Care. 2009;32(7):1320-1326.

Economic and QoL Burden in DD-CKD • Clinical management of CKD-related anemia has substantially changed in the past decade • NDD-CKD and DD-CKD ESA clinical trials demonstrated that aiming for a Hb target ≥13 g/dL resulted in increased CV events, stroke, and death1-4

• Despite the high costs of ESAs, non-treatment of CKDrelated anemia resulted in medical costs and HRU that outweighed ESA costs, in one systematic review5 • Aiming for a Hb target >12 g/dL resulted in higher HRU and costs and translated into higher costs per QALY gained5 CV, cardiovascular; EAS, erythropoietin-stimulating agent; HRU, health resource utilization; QALY, quality-adjusted life year; QoL, quality of life. 1. Drueke TB, et al. N Engl J Med. 2006;355(20):2071-2084. 2. Singh AK, et al. N Engl J Med. 2006;355(20):2085-2098. 3. Pfeffer MA, et al. N Engl J Med. 2009;361(21):2019-2032. 4. Besarab A, et al. N Engl J Med. 1998;339(9):584-590. 5. Spinowitz B, et al. J Med Econ. 2019;22(6):593-604.

Economic Burden of Anemia of CKD • Hospital admissions for patients with CKD who have anemia are 1.3 to 1.4 times greater than for patients with CKD who do not have anemia1 • Annual direct medical costs of managing patients with CKD who have anemia were estimated to be at least $20,000 more than for patients with CKD who do not have anemia2

• Medicare spending for patients with CKD aged ≥65 years exceeded $50 billion in 2013 – Represented 20% of all Medicare spending in this age group3

1. St. Peter WL, et al. BMC Nephrol. 2018;19(1):67. 2. Ershler WB, et al. Value Health. 2005;8(6):629-638. 3. National Institutes of Health. Kidney disease statistics for the United States. www.niddk.nih.gov/health-information/health-statistics/kidney-disease. Accessed May 11, 2020.

Cost of Untreated vs Treated Anemia in Elderly Patients With CKD Claims Data Analysis

â&#x20AC;˘ In an overall CKD population, untreated anemia relative to nonanemia was associated with an unadjusted incremental monthly cost of $1089 Monthly medical costs for untreated anemia periods vs nonanemia periodsa

All patients with CKD Outpatient services Inpatient services Pharmacy costs Total costs

Untreated Anemia Nonanemia Periods Incremental Cost Periods (Mean, 95% CI) (Mean, 95% CI) (C; A-B) (A) (B) 703 (654-752) 1734 (1528-1941) 91 (85-97) 2529 (2285-2772)

489 (471-507) 856 (796-916) 94 (92-97) 1439 (1368-1510)

214 878 -3 1089

Cost Ratio (D; 1+C/B) 1.4b 2.0b 1.0 1.8b

After adjustment for important covariates, the cost burden of untreated anemia was $503 and remained significant. Analysis based on administrative medical and pharmacy claims data. N=2001. a$2529 vs $1439; bP<0.0001 and a cost ratio of 1.8:1 (P<0.0001) relative to nonanemia. Lefebvre P, et al. J Am Soc Nephrol. 2006;17(12):3497-3502.

Assessing Cost-Effectiveness of NDD-CKD Hb Targets

ICERs and QALYs assessed for Hb targets Target Hb 10 g/dL 10.5 g/dL 11 g/dL

Comparator

ICER

QALY

No treatment

$32,111

4.63

Hb target of 10 g/dL

$32,475

4.75

Hb target of 10.5 g/dL

No change from 10.5 g/dL target

In simulated persons aged >30 years with CKD stage 3 or 4, anemia treatment is most cost-effective when targeting a Hb level of 10.5 g/dL. Hb treatment targets >11 g/dL increased medical costs and decreased QALYs. eGFR, estimated glomerular filtration rate; ICER, incremental cost-effectiveness ratio (incremental cost divided by incremental QALYs). CKD Health Policy Model employed, representing persons with eGFR <60 mL/min/1.73 m2 not on dialysis. Model assumes simulated patients receive ESA treatment when Hb <10 g/dL. Iron supplementation begins when patient becomes anemic, and as long as they receive ESA treatment. Yarnoff BO, et al. PLoS ONE. 2016;11(7):e0157323.

Are Hb Levels Associated With Quality of Life?

In patients who have CKD, no significant association between improvements in Hb levels and any of the 5 dimensions of QoL was founda Hematologic Outcome

QoL Domain Physical Mental and emotional Social Fatigue/energy level, vitality Global well-being and QoL

Improvement No Change Improvement No Change Improvement No Change Improvement No Change Improvement No Change

Improvement

No Change

10 6 9 5 4 10 9 7 5 7

2 0 1 1 0 2 1 1 0 1

P>0.05. Systematic review of the use of patient-centered outcomes in patients with CKD who have anemia undergoing treatment for anemia (95% ESAs). Staibano P, et al. Kidney Dis (Basel). 2020;6(2):74-84.

Studies, no. 18 16 16 18 13

CURRENT TREATMENT OPTIONS

ESAs and Iron Supplementation

EPO Analogue Timeline Gene for EPO cloned

Studies report EPO use in renal anemia

Pre-1985

1986

EPO genetically engineered

FDA labeling changed regarding ESA safety

CHOIR and CREATE

1989 FDA approves first ESA

2006

2009

2011

TREAT

CHOIR, Correction of Hemoglobin and Outcomes in Renal Insufficiency; CREATE, Cardiovascular Reduction Early Anemia Treatment Epoetin beta; FDA, US Food and Drug Administration; TREAT, Trial to Reduce Cardiovascular Events with Aranesp Therapy. Adapted from Fishbane S. ASN Kidney News. 2019;11(5):5-6.

CREATE, CHOIR, TREAT

Results from the CREATE, CHOIR, and TREAT trials led to rapid changes in treatment patterns for anemia in patients on hemodialysis: lower ESA doses, lower target Hb levels, greater intravenous iron use, and increased rates of patients receiving RBC transfusion.1-4 1. DrĂźeke TB, et al. N Engl J Med. 2006;355(20):2071-2084. 2. Singh AK, et al. N Engl J Med. 2006;355(20):2085-2098. 3. Pfeffer MA, et al. N Engl J Med. 2009;361(21):2019-2032. 4. Stirnadel-Farrant et al. BMC Nephrol. 2018;19(1):135.

ESA Therapy and Hb Targets FDA Guidance

• For patients not on dialysis – Consider ESA therapy when Hb is <10 g/dL and

• The rate of Hb decline indicates RBC transfusion will likely be required and • Reducing the risk of alloimmunization or other RBC transfusion–related complications is a goal

• For patients on dialysis

– Initiate ESA treatment when the Hb level is <10 g/dL

• If the Hb level approaches or exceeds 11 g/dL, reduce or interrupt the ESA dose

– If Hb level exceeds 10 g/dL, reduce or interrupt the ESA dose and use the lowest dosage of ESA sufficient to reduce the need for RBC transfusions US Food and Drug Administration. Drug safety communication: modified dosing recommendations to improve the safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-modified-dosing-recommendations-improve-safe-useerythropoiesis. Accessed June 20, 2020.

ESA Therapy and Hb Targets KDIGO Guidance

• For patients not on dialysis

– For adult patients with NDD-CKD with Hb concentration <10.0 g/dL, we suggest that the decision to initiate ESA therapy be individualized based on the • • • • •

Rate of fall of Hb concentration Prior response to iron therapy Risk of needing a transfusion Risks related to ESA therapy Presence of symptoms attributable to anemia

• For patients with DD-CKD (stage 5)

– For adult patients with DD-CKD, we suggest that ESA therapy be used to prevent the Hb concentration falling below 9.0 g/dL, by starting ESA therapy when the Hb is between 9.0 and 10.0 g/dL

Maintenance therapy: In general, we suggest that ESAs not be used to maintain Hb concentration >11.5 g/dL in adults with CKD. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. Kidney Int Suppl. 2013;1:279-335.

Advancing Our Understanding of Iron Supplementation PIVOTAL and FIND-CKD Results

“Among patients undergoing hemodialysis, a high-dose intravenous iron regimen administered proactively was noninferior to a low-dose regimen administered reactively and resulted in lower doses of erythropoiesis-stimulating agent being administered.”1

“Compared with oral iron, IV FCM targeting a ferritin of 400–600 μg/L quickly reached and maintained Hb level, and delayed and/or reduced the need for other anaemia management including ESAs. Within the limitations of this trial, no renal toxicity was observed, with no difference in cardiovascular or infectious events.”2

FIND-CKD, Ferinject assessment in patients with Iron deficiency anaemia and Non-Dialysis-dependent Chronic Kidney Disease (FIND-CKD); IV, intravenous; PIVOTAL, Proactive IV irOn Therapy in hemodiALysis patients. 1. MacDougall IC, et al. N Engl J Med. 2019;380(5):447-458. 2. MacDougall IC, et al. Nephrol Dial Transplant. 2014;29(4):843-850.

EMERGING TREATMENT OPTIONS HIF-PH Inhibitors

Novel Class of Agents Target the HIF System HIF Stabilizers Under Investigation

Drug

Regulatory Status

Daprodustat1

In phase 3

Molidustat2

In phase 3

Roxadustat3

• Approved in China and Japan • US FDA PDUFA date December 20, 2020

Vadadustat4,5

Approved in Japan Top-line Phase 3 results reported

Class Comment • Oral dosing • Subtle differences in pharmacokinetics among agents in this class • Minimal transient increase observed in EPO levels

HIF, hypoxia-inducible factor; PDUFA, Prescription Drug User Fee Act. 1. ClinicalTrials.gov. NCT03400033, NCT03029208. 2. ClinicalTrials.gov. NCT03418168, NCT03351166, NCT03350347. 3. Application for Roxadustat for the Treatment of Anemia of Chronic Kidney Disease. San Francisco, Calif. February 11, 2020. https://www.globenewswire.com/news-release/2020/02/11/1983461/0/en/FibroGenAnnounces-U-S-FDA-Acceptance-of-New-Drug-Application-for-Roxadustat-for-the-Treatment-of-Anemia-of-Chronic-Kidney-Disease.html. Accessed May 28, 2020. 4. ClinicalTrials.gov. NCT02892149, NCT02648347. 5. Akebia Therapeutics Announces Positive Top-Line Results from Global Phase 3 Program of Vadadustat for Treatment of Anemia Due to Chronic Kidney Disease in Adult Patients on Dialysis. Cambridge, Mass. May 5, 2020. Press Release. Akebia Therapeutics. https://ir.akebia.com/newsreleases/news-release-details/akebia-therapeutics-announces-positive-top-line-results-global. Accessed June 9, 2020.

Pharmacologic Profiles of HIF Stabilizers in Development Compound

Effective Daily Dosing Plasma Oral Doses in Half-Life (h) Schedule EPO (IU/L) Phase 2 Trials

Daprodustat

5-25 mg (50 and 100 mg also examined)

Molidustat

25-150 mg (>75 mg in DD-CKD)

Roxadustat

0.7-2.5 mg/kg

Vadadustat

150-600 mg

Metabolism

Relative Activity, IC50 for PHD2 (ÂµM)

Approximately 1-7

24.7 and 34.4, 82.4

CYP2C8, with minor CYP3A4

PHD3>PHD1> PHD2, 0.067

4-10

39.8

PHD3>PHD1/2, 0.007

TIW

12-15

113 and 397, 130

CYP2C8

PHD1/2/3 equally, 0.027

QD (TIW)

4.7-9.1

PHD3>PHD1> PHD2, 0.029

CYP, cytochrome P450; IC50, half-maximal inhibitory concentration; NA, not applicable; PHD, prolyl hydroxylase domain; QD, daily; TIW, three times a week. Sanghani NS, Haase VH. Adv Chronic Kidney Dis. 2019;26(4):253-266.

Roxadustat vs Placebo in NDD-CKD OLYMPUS Phase 3 Results

• Greater average mean ΔHb during weeks 28 to 521 – +1.75 g/dL for roxadustat vs +0.40 g/dL for placeboa

• Roxadustat reduced the risk of rescue therapy via1 – RBC transfusion, by 63% (HR=0.37)a – IV iron, by 59% (HR=0.41)a – EPO analogue, by 87% (HR=0.13)a

• Pooled phase 3 data for NDD-CKD (n=4270)2

– Comparable risk for MACE, MACE+, and all-cause mortality with roxadustat vs placebo

ASN, American Society of Nephrology; MACE, major adverse cardiac event; MACE+, major adverse cardiac event plus heart failure or unstable angina requiring hospitalization. aP<0.001 for roxadustat vs placebo. 1. Fishbane S, et al. OLYMPUS: Presented at: ASN Kidney Week; November 5-10, 2019; Washington, DC. Abstract TH-OR023. 2. Provenzano R, et al.. Presented at: ASN Kidney Week; November 5-10, 2019; Washington, DC. Abstract FR-OR131.

Roxadustat vs EPO in DD-CKD ROCKIES Phase 3 Results

• Greater average mean ΔHb during weeks 28 to 521 – +0.77 g/dL for roxadustat vs +0.68 g/dL for EPOa

• Less monthly IV iron from week 36 to end of study1 – 58.7 mg for roxadustat vs 91.4 mg for EPOb

• Similar percentage of patients received RBC transfusion with roxadustat and EPO (HR=0.83)1 • Pooled phase 3 data for DD-CKD (n=3917)2

– Comparable risk for MACE and all-cause mortality with roxadustat vs EPO – Lower risk for MACE+ with roxadustat vs EPO (HR=0.84)a

for roxadustat vs EPO; bP<0.0001 for roxadustat vs EPO. 1. Fishbane S, et al. ROCKIES: An International, Phase 3, Randomized, Open-Label, Active-Controlled Study of Roxadustat for Anemia in Dialysis-Dependent CKD Patients. Presented at: ASN Kidney Week; November 5-10, 2019; Washington, DC. Abstract TH-OR022. 2. Provenzano R, et al. Presented at: ASN Kidney Week; November 5-10, 2019; Washington, DC. Abstract FR-OR131. aP<0.05

Roxadustat vs EPO in Incident (<4 Months) Dialysis CKD HIMALAYAS Phase 3 Results

• ESA-naive or limited prior use1 • Greater average mean ΔHb during weeks 28 to 521 – +2.57 g/dL for roxadustat vs +2.36 g/dL for EPOa

• Pooled phase 3 data for incident dialysis CKD (n=1526)2 – Lower risk with roxadustat vs EPO for MACE (HR=0.70b) and MACE+ (HR=0.66c)

for roxadustat vs EPO; bP=0.03 for roxadustat vs EPO; cP=0.005 for roxadustat vs EPO. 1. Provenzano R, et al. Presented at: ASN Kidney Week; November 5-10, 2019; Washington, DC. Abstract TH-0R021. 2. Provenzano R, et al. Presented at: ASN Kidney Week; November 5-10, 2019; Washington, DC. Abstract FR-OR131. aP=0.0005

Roxadustat Adverse Events in NDD-CKD Roxadustat Phase 3 Results Roxadustat (n=101)

Placebo (n=51)

n (%)

37 (37)

25 (49)

Anemia

3 (6)

Diarrhea

3 (6)

Peripheral edema

7 (7)

3 (6)

Pyrexia

2 (2)

3 (6)

Upper respiratory tract infection

5 (5)

4 (8)

Hyperkalemia

16 (16)

4 (8)

Metabolic acidosis

12 (12)

1 (2)

Gout

1 (1)

3 (6)

Back pain

0 (0)

3 (6)

Dizziness

1 (1)

4 (8)

Hypertension

6 (6)

2 (4)

Any Adverse Event

Chen N, et al. N Engl J Med. 2019;381(11):1001-1010.

ASSESSING COST-EFFECTIVENESS OF HIF-PH STABILIZERS

Snapshot of Cost-Effectiveness

Roxadustat vs Placebo of NDD-CKD in China Strategy Placebo Roxadustat

Cost (US $)

Incremental Cost (US $)

1756 14,282

Incremental Effectiveness Effectiveness (QALYs) (QALYs)

ICER (US $/ QALYs)

2.87 12,526

3.36

0.49

25,563

Oral roxadustat at 70 mg three times weekly had 60% probability of being costeffective, compared with placebo using conventional WTP thresholds (in China) to treat anemia in patients with NDD-CKD. Average QALY of Hb level of 9.5 to be equal to that of the Hb level group (<11 g/dL: 0.633), and a Hb level of 11.5 to be equal to that of the Hb level group (11-12 g/dL: 0.689); then the QALY decrement per 1 g/dL decrease in Hb level was (0.689–0.633)/(11.5–9.5)=0.028. Mean basic Hb level in the model was 8.9 g/dL, assuming that the QALY in this model when Hb <10 g/dL was calculated as 0.633–0.028×(9.5–8.9)=0.616, whereas Hb 10-12 g/dL was to be 0.689–0.028×(11.5–11.0)=0.675. Hu S, et al. Expert Rev Pharmacoecon Outcomes Res. 2020. doi:10.1080/14737167.2020.1747436.

Determining Cost-Effectiveness of Treatments in CKD

• Clinical guidelines have not considered incremental costeffectiveness when recommending Hb treatment targets • A validated anemia PRO or standardized set of QoL tools used across studies is needed • Compare incremental costeffectiveness of new HIF-PHIs with ESAs in the US PRO, patient reported outcome Uarnoff BO, et al. PLoS ONE. 2016;11(7):e0157323.