hif prolyl hydroxylase inhibitors -...
TRANSCRIPT
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HIF prolyl hydroxylase
inhibitors
11th May 2017
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Erythropoiesis stimulating agents in renal anemia
Anaemia is a cardinal feature of chronic kidney disease
Primarily due to impaired erythropoietin production
Until late 1980’s
Regular transfusion
Immune sensitisation, iron overload, Hepatitis B & C
For most patients - chronic anaemia
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Effect on life, and on combustion
1977
1987 Used in humans with kidney disease
2003 $10bn per annum
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Problems with ESA’s in renal anemia
Require injection
Difficult to manufacture, store
Many patients require iv iron
Primary red cell aplasia (~1 in 10,000 years)
Targeting normal haematocrit associated with increased CV events
FDA Black box warning
Revised targets
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Besarab et al New Engl J Med 1998
Normal HCT trial – 42% vs 30%
Risk ratio 1.3 (0.9 – 1.9)
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Pfeffer et al New Engl J Med 2009
TREAT: CKD + DIABETES Hb rescue at 9 g/dl vs 13 g/dl
CHOIR: 11.3 vs 13.5 Higher rate of CV events
Singh et al New Engl J Med 2006
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Why is treatment to a higher haematocrit associated
with increased cardiovascular events?
1. An effect of supraphysiological erythropoietin levels
2. Related to iron supplementation
3. Subnormal haematocrit may be beneficial in CKD
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Ben Foster as Lance Armstrong in The Program, 2015
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Less oxygen
More erythropoietin
1% O2
ONHREErythropoietin gene
OFF
21% O2
HREErythropoietin gene
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HIF-1bHIF-a
HRE
HIF-2a
Wiesener et al, Blood 1998
Hypoxia Inducible Factor (HIF)
Transcription factor regulated via destruction of a subunit
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von Hippel-Lindau disease
Autosomal dominant
1 in 36,000
Retinal angiomas
Renal cell carcinoma
Gene cloned in 1993
mutated / inactivated in ~ 80% of sporadic clear cell kidney cancer
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Knudson’s two hit model
Recessive at a cellular level
Mutated / inactivated in ~ 80% of sporadic clear cell renal carcinomas
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Maxwell et al, Nature 1999
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O2HIFa Pro564
HIFa Hyp564
UbUb
Ub
Rbx1
Cul2Elongin
BC
E2/E1
HIFa
VHL
Hyp564
UbUb
Ub
HIFa
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C. elegans - evolutionary conservation of the HIF system
Epstein et al, Science 2001
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Three closely related isoforms are
mammalian homologues of EGL-9
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O2
Fe
HIFa Pro564
2oxoglutarate
PHD
CO2
Fe
HIFa Hyp564
succinate
PHD
UbUb
Ub
Rbx1
Cul2Elongin
BC
E2/E1
HIFa
VHL
Hyp564
UbUb
Ub
HIFa
Three PHD enzymes
Two HIFa subunits
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Vasomotor
NOS isoforms
Endothelins
Adrenoreceptors
Tyrosine hydroxylase
Blood oxygen
Erythropoietin
Metal transport
Transferrin
Caeruloplasmin
Angiogenesis
VEGF
PLGF
PDGF
Matrix metabolism
Collagens/prolyl hydroxylases
Transglutaminase
Cell proliferation/survival
IGF/IGF-BPs
Cyclin G2
Nip/Nix
Energy metabolism
Glucose transporters
Glycolytic enzymes
TranscriptionHIF-1bHIF-1a
coactivators
HRE
HIF regulates hundreds of genes
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Small molecule PHD inhibitors activate HIF
Jaakkola et al, Science
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HIF has many targets
PHD’s may regulate other pathways
HIF-1 other PHD targets HIF-2
Many structurally related enzymes
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Autosomal recessive - Hypomorphic VHL allele. Chuvash polycythaemia
Autosomal dominant - Haploinsufficiency. PHD2 erythrocytosis
Autosomal dominant - Gain of function. HIF2A erythrocytosis
Modest HIF activation / PHD2 inactivation is sufficient to increase haematocrit
Validates HIF2 activation and PHD2 inhibition as a therapeutic strategy
Genetic HIF activation in humans
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A small molecule PHD inhibitor, FG-2216
increases EPO in humans
Normal volunteers
Dialysis patients
with kidneys in situ
Dialysis patients
Without kidneys
Bernhardt et al J Am Soc Nephrol 2010
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On target effects – mouse studies
HIF-1 other PHD targets HIF-2
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+/- -/-+/+
Inheritance in PHD-deficient mice
PHD-1 (135) 22% 55% 23%
PHD-2 (331) 38% 62% 0%
PHD-3 (186) 31% 51% 18%
On target effects of PHD enzyme removal
Aragones et al Nature Genetics
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Wild typephd2 -/-
PHD2 (and HIF-2a) major regulators of
haematocrit
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Loss of PHD1 protects against ischemic muscle
necrosis
WT gastrocnemius muscle PHD1-/- gastrocnemius
muscle
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Loss of PHD1 protects ischaemic skeletal muscle
Aragones et al Nature Genetics 2008
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Hill et al, J Am Soc Nephrol 2008
PHD inhibitors protect from renal IRI
HIF is not fully activated in complete ischemia
HIF1 or HIF2 heterozygosity exacerbates renal IRI
DMOG, L-mimosine activate HIF-a in IRI
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DMOG Saline
Hill et al, J Am Soc Nephrol 2008
PHD inhibitors protect from renal IRI
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Casts Tubular Dilatation
Treated TreatedUntreated Untreated
Casts
Treated U ntr ea te d0
1
2
3
4Treated
Untreated
Score
P<0.0001
Score
Score
Tubular Dilatation
Trea ted Unt re a te d0
1
2
3
4Treated
Untreated
P<0.0001
Score
Hill et al J Am Soc Nephrol 2008
PHD inhibitors from renal IRI
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Necrosis
PHD-1 WT0
1
2
3P<0.001
Sco
re
Brush Border
PHD-1 WT0
1
2
3
4P<0.001
Sco
re
Casts
PHD-1 WT0
1
2
3
4P<0.001
Sco
re
Dilated tubules
PHD-1 WT0
1
2
3
4P<0.001
Sco
re
Loss of PHD1 protects from renal IRI
WTPHD1-/- WTPHD1-/-
WTPHD1-/- WTPHD1-/-
Peter Hill unpublished data
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Casts
0
1
2
3
Brush Border
0
1
2
3
Dilated Tubules
0
1
2
3
4
Necrosis
0
1
2
3
PHD3 -/- WT PHD3 -/- WT
PHD3 -/- WT PHD3 -/- WT
Loss of PHD3 exacerbates renal IRI
Peter Hill unpublished data
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Mouse knockout: myocardial damage is reduced
after cardiac ischemia/reperfusion in PHD3-/- mice
PHD WT PHD3-/-
PHD
WT
PHD3-/-
40
30
20
10
0Infa
rcte
d /
to
tal a
rea
x 1
00
P < 0.01
Peter Carmeliet unpublished data
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Autosomal dominant - Cellular recessive / 2 hit. Von Hippel Lindau disease
Cerebellar, retinal haemangioblastoma; renal cysts, tumors:
pheochromocytoma
Not inherited - 70% of clear cell renal cancer. Two somatic VHL hits.
Autosomal recessive - Hypomorphic VHL allele. Chuvash polycythaemia
Autosomal dominant - Haploinsufficiency. PHD2 erythrocytosis
Autosomal dominant - Gain of function. HIF2A erythrocytosis
Valuable for defining physiological role
Chuvash: haemangiomas, thromboses, varicose veins, shortened lifespan,
altered cytokines
On target effects in humans
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Very large numbers of foci of HIF activation
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Proximal tubule
Distal tubule
Minimal proliferation
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HIF2α
Gale et al, Blood 2008
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“An activating mutation in HIF2A would be too good to be true”
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*
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Associated with severe pulmonary hypertension
Confirmed in humans and mice with Chuvash
polycythaemia & VHL compound heterozygotes
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• key component of the classical complement pathway
• Is involved in several other immunological processes
maintenance of immune tolerance via clearance of apoptotic cells,
phagocytosis of bacteria
neutralization of retroviruses,
cell adhesion,
modulation of dendritic cells (DCs), B cells and fibroblasts
• C1q can engage a broad range of ligands
Immunoglobulins
envelope proteins of certain retroviruses,
lipopolysaccharides (LPS), porins from Gram-negative bacteria,
phospholipids (PL), apoptotic cells.
Example off target effect - complement C1q
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Structural organization of the C1q molecule
460 kd
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U
IFN
/DM
OG
IFN
0
10
20
30
Untreated
IFN
IFN/DMOG
***
C1
q (
ng
/ml)
20% O2 1% O2
IFN - + + - + +
DMOG - - + - - +
HIF-1a
a-tubulin
C1q expression by THP-1 derived macrophages is sensitive to DMOG
Kiriakidis et al, Kidney Intl in press
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N N+IFN H H+IFN0
25
50
75
100
C1q
(U
/ml)
C1q expression by THP-1 derived macrophages is resistant to hypoxia
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P4HA1 is present in macrophages and necessary for C1q secretion
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Small molecule PHD inhibitors reduce C1q through an off target effect
on P4HA1
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Phase I + II Tolerated, safe and effective
Phase III in progress
PHD inhibitors 2017
AKB-6548/vadadustat
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PHD inhibitors in renal anemia
Orally active
Manufacturing, stability
Less intravenous iron required
Critical question in Phase 3 trials
Cardiovascular endpoints / mortality compared with ESA
Effects on blood pressure, lipids, inflammation, cancer….?
Unusual target for pharma: on-target + off-target effects
Activating a pathway rather than inhibiting
“Tickling the target”
What is your prediction?
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PHD inhibitors in ischemia
Major unmet medical need – stroke, claudication, ulcers
PHD1 looks like a good choice
Inhibition of C1q may be advantageous
Track record of translation from animal models is very poor
Dose, timing etc may be critical
Route to market is unclear
Market size is unclear
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Summary and conclusions
1. Many processes, including erythropoiesis, regulated by oxygen
tension
2. Underpinned by PHD enzymes, which are druggable
3. PHD inhibitors are effective in increasing haematocrit, and are well
tolerated
4. Currently being tested vs ESA’s as a treatment for renal anaemia.
Included in doping controls. Benefits vs risks likely to vary.
5. Likely to be attractive in other settings
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Acknowledgements
Chris Pugh, Peter Ratcliffe, Chris Schofield, David Mole, Peter Robbins
Peter Carmeliet, Dominic Withers, James Cantley, Colin Selman, Melanie Percy,
Mary-Francis McMullin, Ted Tuddenham, John Chambers, Jaspal Kooner,
Roberto Mayor, Margaret Ashcroft
Frauke Forstreuter, Sarah Harten, Tapan Bhattacharyya, Reiko Ueki, Maxine
Tran, Peter Hill, Ravi Barod, Daniel Gale, Deepa Shukla, Daz Khan, Serafim
Kiriakidis, Simon Hoer, Natalie Burrows
With financial support from the MRC, EU, Wellcome Trust, CRUK, Imperial and
the BHF.
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In kidney Epo-producing cells are cortical / OM fibroblasts
Maxwell et al, KI, 1993