11 th May HIF prolyl hydroxylase inhibitors
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1 11 th May 2017 HIF prolyl hydroxylase inhibitors
2 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
3 Used in humans with kidney disease 2003 $10bn per annum Effect on life, and on combustion
4 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
5 Normal HCT trial 42% vs 30% Risk ratio 1.3 ( ) Besarab et al New Engl J Med 1998
6 TREAT: CKD + DIABETES Hb rescue at 9 g/dl vs 13 g/dl Pfeffer et al New Engl J Med 2009 CHOIR: 11.3 vs 13.5 Higher rate of CV events Singh et al New Engl J Med 2006
7 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
8 Ben Foster as Lance Armstrong in The Program, 2015
9 Less oxygen ON Erythropoietin gene HRE 1% O 2 More erythropoietin OFF Erythropoietin gene HRE 21% O 2
10 Hypoxia Inducible Factor (HIF) HIF-1b HRE HIF-a HIF-2 a Wiesener et al, Blood 1998 Transcription factor regulated via destruction of a subunit
11 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
12 Knudson s two hit model Recessive at a cellular level Mutated / inactivated in ~ 80% of sporadic clear cell renal carcinomas
13 Maxwell et al, Nature 1999
14 HIFa Pro564 O 2 HIFa Hyp564 HIFa HIFa VHL Hyp 564 Cul2 Elongin BC Rbx1 Ub Ub Ub Ub Ub Ub E 2 /E 1
15 C. elegans - evolutionary conservation of the HIF system Epstein et al, Science 2001
16 Three closely related isoforms are mammalian homologues of EGL-9
17 Three PHD enzymes PHD Fe HIFa Pro564 O 2 2oxoglutarate PHD Fe HIFa Hyp564 succinate CO 2 Two HIFa subunits HIFa HIFa VHL Hyp 564 Cul2 Elongin BC Rbx1 Ub Ub Ub Ub Ub Ub E 2 /E 1
18 HIF regulates hundreds of genes Blood oxygen Erythropoietin Angiogenesis VEGF PLGF PDGF Energy metabolism Glucose transporters Glycolytic enzymes HIF-1b HRE coactivators HIF-1a Transcription Vasomotor NOS isoforms Endothelins Adrenoreceptors Tyrosine hydroxylase Metal transport Transferrin Caeruloplasmin Cell proliferation/survival IGF/IGF-BPs Cyclin G2 Nip/Nix Matrix metabolism Collagens/prolyl hydroxylases Transglutaminase
19 Small molecule PHD inhibitors activate HIF Jaakkola et al, Science
20 HIF has many targets PHD s may regulate other pathways HIF-1 other PHD targets HIF-2 Many structurally related enzymes
21 Genetic HIF activation in humans 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
22 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
23
24 On target effects mouse studies HIF-1 other PHD targets HIF-2
25 On target effects of PHD enzyme removal +/+ +/- -/- PHD-1 (135) 22% 55% 23% PHD-2 (331) 38% 62% 0% PHD-3 (186) 31% 51% 18% Inheritance in PHD-deficient mice Aragones et al Nature Genetics
26 Wild type phd2 -/- PHD2 (and HIF-2a) major regulators of haematocrit
27 Loss of PHD1 protects against ischemic muscle necrosis WT gastrocnemius muscle PHD1 -/- gastrocnemius muscle
28 Loss of PHD1 protects ischaemic skeletal muscle Aragones et al Nature Genetics 2008
29 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 Hill et al, J Am Soc Nephrol 2008
30 PHD inhibitors protect from renal IRI DMOG Saline Hill et al, J Am Soc Nephrol 2008
31 Score Score PHD inhibitors from renal IRI Casts Tubular Dilatation Tubular Dilatation e r o c S P< e r o c S 4 Treated 3Untreated 2 1 P< Treated Untreated 0 Treated Untreated 0 Treated Untreated Hill et al J Am Soc Nephrol 2008
32 Score Loss of PHD1 protects from renal IRI Necrosis Brush Border P< P< Score PHD-1 PHD1-/- WT WT 0 PHD-1 PHD1-/- WT WT 4 Casts P< Dilated tubules P< Score 2 Score PHD-1 PHD1-/- WT WT 0 PHD-1 PHD1-/- WT WT Peter Hill unpublished data
33 Loss of PHD3 exacerbates renal IRI Necrosis Brush Border PHD3 -/- WT PHD3 -/- WT 0 3 Casts 4 Dilated Tubules PHD3 -/- WT PHD3 -/- WT 0 Peter Hill unpublished data
34 Infarcted / total area x 100 Mouse knockout: myocardial damage is reduced after cardiac ischemia/reperfusion in PHD3 -/- mice 40 P < PHD WT PHD3 -/- PHD WT PHD3 -/- Peter Carmeliet unpublished data
35 On target effects in humans 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
36 Very large numbers of foci of HIF activation
37 Minimal proliferation Proximal tubule Distal tubule
38
39 HIF2α Gale et al, Blood 2008
40 An activating mutation in HIF2A would be too good to be true
41 *
42 Associated with severe pulmonary hypertension Confirmed in humans and mice with Chuvash polycythaemia & VHL compound heterozygotes
43 Example off target effect - complement C1q 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.
44 Structural organization of the C1q molecule 460 kd
45
46 C1q expression by THP-1 derived macrophages is sensitive to DMOG 30 Untreated IFN IFN /DMOG C1q (ng/ml) % O 2 1% O 2 IFN DMOG HIF-1a 0 U IFN *** IFN /DMOG a-tubulin Kiriakidis et al, Kidney Intl in press
47 C1q expression by THP-1 derived macrophages is resistant to hypoxia 100 C1q (U/ml) N N+IFN H H+IFN
48 P4HA1 is present in macrophages and necessary for C1q secretion
49 Small molecule PHD inhibitors reduce C1q through an off target effect on P4HA1
50 PHD inhibitors 2017 AKB-6548/vadadustat Phase I + II Tolerated, safe and effective Phase III in progress
51 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?
52 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
53 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
54 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.
55 In kidney Epo-producing cells are cortical / OM fibroblasts Maxwell et al, KI, 1993
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