Transcript HIF-PH Inhibitors and Hepcidin Levels

Updates From Kidney Week
Chronic Kidney Disease and
Associated Anemia
Moderator
Steven N. Fishbane, MD
Professor of Medicine
Hofstra Northwell School of Medicine
Chief, Division of Kidney Diseases and Hypertension
North Shore University Hospital
Long Island Jewish Medical Center
Great Neck, New York
Panelists
Jeffrey S. Berns, MD
Myles S. Wolf, MD
Professor of Medicine
Associate Dean for Graduate Medical
Education
University of Pennsylvania
Director
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Professor of Medicine
Chief of Nephrology
Duke University School of Medicine
Durham, North Carolina
This program will include a discussion
of off-label treatment options and
investigational agents not yet
approved by the FDA for use in the
United States.
There will also be a discussion of data
that were presented in abstract form.
These data should be considered
preliminary until published in a
peer-reviewed journal.
Introduction
• Anemia is a frequent and significant complication
of CKD
– Associated with a high prevalence of cardiovascular
disease in this patient population
• There are a number of options for treating anemia
in this patient population; however, there continue
to be limitations with current treatments
Pattern Changes in Anemia Treatment
in Patients With NDD-CKD
Objective
• Evaluate the use and time to use of ESA, IV iron, and
RBC transfusion after diagnosis of anemia during
baseline year
Methods
• Two study cohorts of Medicare patients with stage 3 to
5 NDD-CKD and anemia
• 2008: 71,744
• 2012: 109,251
• Consistent ESA treatment: ≥1 ESA monthly
administration in ≥80% of 12 follow-up months
Results
• ESA use decreased by 57% from 2008 to 2012
• IV iron use and RBC transfusions remained stable
• Patients received transfusions sooner, corresponding to
decline in ESA use
St Peter WL, et al. J Am Soc Nephrol. 2016;27. Abstract FR-PO767.
Changes in ESA Labels
• 2011 FDA update for ESA use in patients with CKD
– Start ESA treatment when the hemoglobin level is
<10 g/dL
– Does not specify if goal is Hb of ≥10 g/dL
– Dosing should be individualized
– Use lowest dose of ESA sufficient to reduce the need
for RBC transfusions
– Adjust dosing as appropriate
FDA website.
Unexpected Medical Consequences
of Revised ESA Label
–
–
–
–
HE ↑ 100%
DVT ↑31%
PE ↑45%
All-cause death and
MACE incidence did
not decline
2008 (n = 71,744)
2012 (n = 109,251)
35
30
Patients, %
• Objective: Examine the
changes in treatment of
anemia, comorbidities and
outcomes after FDA label
revisions for ESA use in
patients with NDD-CKD
and anemia
• CV outcomes in the 2012
cohort:
25
20
15
10
5
0
ESA
Li S, et al. J Am Soc Nephrol. 2016;27. Abstract SA-PO795.
IV Iron
RBC
Transfusion
Decrease in Adverse Events Post-FDA
Label Changes to ESA Treatment
Patient
population
Reduction in
events
Chertow, et al[a]
Wang, et al[b]
≈ 250,000 patients receiving
maintenance dialysis between
2005 and 2012
69,718 patients who had
undergone incident
hemodialysis between
2008 and 2013
Absolute deviation
from trend per 100 patient-years
(95% CI):
• Stroke: -0.24 (-0.08, -0.37)
• VTE: -2.43 (-1.35, -3.70)
• Heart failure: -0.77 (-0.28, -1.27)
Decreased risk of stroke
(HR: 0.77, 95% CI: 0.64,
0.93; P = .01)
a. Chertow GM, et al. J Am Soc Nephrol. 2016;27:3129-3138.
b. Wang C, et al. JAMA Intern Med. 2016;176:1818-1825.
Use of High ESA Doses in Patients With
NDD-CKD
Objective
Methods
• Looked at the
association of
increased adverse
events,
comorbidities, and
healthcare resource
utilization in patients
with NDD-CKD and
anemia
2011-2013 Medicare
data
• 12,901 patients with
stage 3-5 NDD-CKD
with anemia
receiving ESAs
• Definition of high
dose ESA: average
monthly ESA dose
>90th percentile of
monthly doses
Gilbertson DT, et al. J Am Soc Nephrol. 2016;27. Abstract SA-PO794.
Results
High dose ESA was
associated with:
• Significantly
increased burden
of CV and
thromboembolic
events
– 60% ↑ risk of death
– 46% ↑ risk of major
cardiac event
– 52% ↑ in Medicare
payments
Role of HIF and HIF-PH in Erythropoiesis
HIF-α
Low Oxygen
Normal Oxygen
(eg, high altitude)
HIF-PH Enzymes
HIF-α
HIF-α
HIF-PH Enzymes
HIF-α degrades
rapidly
HIF-α
Gene Transcription
Degradation
HIF-β
Effect of Vadadustat* on Hemoglobin
Levels in Patients With DD-CKD
• Randomized, phase 2 open-label study
• Objective: assess Hb response to 3 starting doses of
vadadustat over 16 weeks in 94 DD-CKD patients
who were maintained on ESAs prior to study entry
• Hb response and vadadustat dose requirements for
Hb maintenance are independent of underlying
systemic inflammation and baseline ESA dose in
patients with DD-CKD
*This agent is not approved by the FDA for use in the United States.
Haase VH, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO960.
Effect of Daprodustat* on Hemoglobin
Maintenance
• Objective: examine the relationship between the dose of
daprodustat and hemoglobin at 4 weeks, and safety and
efficacy over 24 weeks
• Participants: 216 subjects on HD previously receiving
recombinant human EPO
• Results
– Switching from a stable dose of EPO to daprodustat produced dosedependent mean changes in Hb from baseline after week 4
– Hepcidin levels were reduced at week 24 (20.6% in daprodustat
group vs 3.6% in control group)
– Adverse event profile in daprodustat group was consistent with the
HD population
*This agent is not approved by the FDA for use in the United States.
Cobitz, AR, et al. J Am Soc Nephrol. 2016;27. Abstract SA-OR114.
Treatment of CKD-Associated Anemia
With Roxadustat* in Patients Not on
Dialysis
–
–
Dose-dependent
increase in hemoglobin
No MACE occurred in
roxadustat group
Change in Hemoglobin, g/dL/wk
• Phase 2, double-blind,
24-week study
• Objective: evaluate safety
and efficacy of roxadustat
• Participants: 107 Japanese
patients with NDD-CKD
and anemia
• Results
P < .0001 for all doses of
roxadustat compared with
placebo
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
-0.1
Roxadustat Roxadustat Roxadustat
50 mg
70 mg
100 mg
n=27
n=26
*This agent is not approved by the FDA for use in the United States.
Akizawa T, et al. J Am Soc Nephrol. 2016;27. Abstract FR-PO1142.
n=27
Placebo
n=27
Potential Future of HIF-PH Inhibitors
• Individuals living at high altitudes have HIF stabilization and
elevated erythropoietin levels[a]
– Can HIF-PH inhibitors used concomitantly with
ESAs diminish adverse events of ESAs and
increase erythropoietin?
• Larger phase 3 trials are necessary to determine safety of
this drug class
– Potential to increase VEGF production (can enhance tumor
progression)[b]
– HIF is also involved in vascular tone and blood pressure
regulation (concern for development of pulmonary
hypertension)[c]
a. Hopfl G, et al. Hypoxia: Through the Lifecycle. 2003:89-115; b. Krock BL, et al.
Genes Cancer. 2011;2:1117-1133; c. Semenza GL. Annu Rev Pathol. 2014;9:47-71.
HIF-PH Inhibitors and Hepcidin Levels
• Hepcidin is a small peptide produced in the liver
• Regulates iron homeostasis
• In CKD, hepcidin levels go up as a result of
decreased renal clearance and inflammation
– Decrease in duodenal absorption of iron
– Iron release from storage sites blocked
• HIF-PH inhibitors play a role in decreasing levels
of hepcidin
Ganz T, et al. Semin Nephrol. 2016;36:87-93.
Maxwell PH, et al. Nat Rev Nephrol. 2016;12:157-168.
Effects of Ferric Citrate* in the
Treatment of Iron Deficiency Anemia in
Patients With NDD-CKD
• 234 patients with NDD-CKD stages 3 to 5 and iron deficiency
anemia randomized to ferric citrate or placebo for 16 weeks
– 52.1% (ferric citrate) vs 19.1% (placebo) achieved ≥1 g/dL increase
in hemoglobin
– 48.7% (ferric citrate) vs 14.8% (placebo) achieved a sustained
increase in hemoglobin
• Most common adverse events are GI (diarrhea, nausea,
constipation)
*This drug is currently not approved by the FDA for this indication.
Fishbane S, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO901.
Regulation of FGF23 and Iron Status
• FGF23 is an endocrine hormone secreted by osteocytes
and osteoblasts
• It is involved in regulating serum phosphate
– Increases fractional phosphate excretion and reduces serum
phosphate levels
• Levels increase as kidney function declines
• FGF23 plays a role in the pathogenesis of left ventricular
hypertrophy, a risk factor for mortality in CKD
• Iron deficiency, as well as some IV iron preparations, can
lead to an increase in FGF23 production
Wolf M. Kidney Int. 2012;82:737-747.
Iron Therapy and Fibroblast Growth
Factor-23 in Hemodialysis
Objective
• Evaluate effect of IV iron on levels of iFGF23 and cFGF23
in hemodialysis patients
– Serum hepcidin, ferritin, and PO4 were also measured
Results
• IV ferric carboxymaltose group (n=22)
– Ferritin and hepcidin levels increased significantly
– cFGF23 increased
– iFGF23 and PO4 decreased
• Iron sucrose group (n=20)
– Ferritin and hepcidin levels increased significantly
Roberts MA, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO539.
Concluding Remarks
• Over the years there have been treatment
pattern changes seen with the use of ESAs
• HIF-PH inhibitors are a newer class of drugs with
potential for treating anemia
• Ferric citrate currently acts as a phosphate binder
but can potentially be used for the treatment of
anemia
• Recent data suggest that iron deficiency and
elevated phosphate levels stimulate FGF23
production
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