Recent early clinical drug development for acute kidney injury
Kevin Gallagher1*, Stephen O'Neill1, Ewen M Harrison1, James A Ross2, Stephen J Wigmore1, Jeremy Hughes1
1MRC Centre for Inflammation Research, University of Edinburgh, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SA
2MRC Centre for Regenerative Medicine, University of Edinburgh, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4S
*Corresponding author: Kevin Gallagher, MRC Centre for Inflammation Research, Tissue Injury and Repair Group, University of Edinburgh, Chancellor’s Building, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SA
Tel: 0044-7849592113
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Key words: Acute kidney injury, alkaline phosphatase, α-melanocortin receptor 1, bone morphogenetic protein receptor, cardiac surgery AKI, delayed graft function, hepatocyte growth factor, p53, sepsis associated AKI.
Abstract
Introduction:Despite significant need and historical trials, there are no effective drugs in use for the prevention or treatment of acute kidney injury (AKI). There are several promising agents in early clinical development for AKI and two trials have recently been terminated.There are also exciting new findings in pre-clinical AKI research. There is a need to take stock of current progress in the field to guide future drug development for AKI.
Areas covered: The main clinical trial registries, PubMed and pharmaceutical company website searches were used to extract the most recent clinical trials for sterile, transplant and sepsis-associated AKI. We summarise the development of the agents recently in clinical trial, update on their trial progress, consider reasons for failed efficacy of two agents, and discuss new paradigms in pre-clinical targets for AKI. Agents covered include- QPI-1002, THR-184, BB-3, hemearginate, human recombinant alkaline phosphatase (recAP), ciclosporin A, AB103, levosimendan, AC607and ABT-719.
Expert Opinion: Due to the heterogenous nature of AKI, agents with the widest pleiotropic effects on multiple pathophysiological pathways are likely to be most effective. Linking preclinical models to clinical indication and improving AKI definition and diagnosis are key areas for improvement in future clinical trials.
AbbreviationsAKI / Acute kidney injury
AKIN / Acute kidney injury network
Alk3 / Acitvin-like kinase 3
AP / Alkaline phosphatase
BM-MSCs / Bone marrow derrivedmesenchymal stem cells
BMP / Bone morphogenetic protein
CKD / Chronic kidney disease
CRP / C-reactive protein
CS-AKI / Cardiac surgery associated AKI
CypD / Cyclophilin D
DAMP / Damage associated molecular pattern
DBD / Donation after brain stem death
DGF / Delayed graft function
eGFR / Estimated glomerular filtration rate
ESRF / End-stage renal failure
HGF / Hepatocyte growth factor
HO-1 / Heme-oxygenase-1
ICU / Intensive care unit
IL / Interleukin
IRI / Ischemia reperfusion injury
KDIGO / Kidney disease improving global outcomes
KIM-1 / Kidney injury molecule 1
LPS / Lipopolysaccharide
MCP-1 / Monocyte chemoattractant protein 1
MLKL / Mixed lineage kinase like domain
MPTP / Mitochondrial permeability transition pore
MSH / Melanocortin stimulating hormone
NGAL / Neutrophil Gelatinase-Associated Lipocalcin
NSTI / Necrotising soft tissue infection
PARP-1 / Poly[ADP-ribose] polymerase 1
PBMC / Peripheral blood mononucear cells
PTEC / Proximal tubular epithelial cell
RCT / Randomised controlled trial
recAP / Recombinant alkaline phosphatase
RIPK / Receptor interacting serine-threonine protein kinase
ROS / Reactive oxygen species
RRT / Renal replacement therapy
SA-AKI / Sepsis associated AKI
TGFB / Transforming growth factor beta
TGF-β / Transforming growth factor beta
TLR / Toll-like receptor
Article highlights
- Comprehensive review of agents currently in clinical trial for transplant, sterile and sepsis associated AKI
- Up to date information on trial progress
- Review of AC607 and ABT-719 two recent failed drugs
- Integration of new pathophysiological understanding of cell death pathways with current agents
- Expert opinion on the way forward in therapeutics for AKI
1Introduction
An episode of Acute Kidney Injury Network (AKIN) criteria 2 (moderate) acute kidney injury (AKI) is associated with 12 timesincreased likelihood of in hospital death (1). Any AKI (AKIN 1) is associated with increased 30-day, 90-day and 10-year mortality rates, increased length of hospital stay and increased hospital readmissions (1, 2). There is increasing recognition that AKI has acute secondary effects such as increasing the incidence of sepsis, acid base disturbances and fluid overload (3). It is also known that AKI contributes to the development of chronic kidney disease (CKD) and end-stage renal failure (ESRF). Preventing AKI or limiting its severity is likely to reduce short and long term mortality, morbidity and healthcare burden (4).Results from the large multi-centre non-pharmacological preconditioning trials for AKI in cardiac surgery were mixed(5-7)and there are a number of historical drug trials (8). There are currently no effective pharmacological agents used clinically for AKI.
AKIhas many aetiologies that affect native kidneys such as ischemia reperfusion injury (IRI), sepsis associated AKI (SA-AKI), and drug toxicity. IRI in transplanted kidneys is also a form of AKI and can result in delayed graft function (DGF).
Within each AKI aetiology there are multiple pathophysiological pathways that may be activated to varying degrees in different patients. The phenotype in patients is not only heterogeneousbut difficult to define, measure and quantify. This leads to the challenges of identifying suitable drug targets (9) and modelling human AKI in animals (10). This makes designing trials that include suitable patients, identify and stratify cases of AKI in meaningful ways and measure the most clinically relevant outcomes problematic to achieve(8).
Drugs for AKI can be primarily preventative, preventative and therapeutic or therapeutic alone. Preventative drugs are used in situations where AKI is predictable such as cardiac surgery or kidney transplantation. Therapeutic agents may also be used in these settings and rather than given to all patients, are given once biochemical evidence of AKI has developed. As has become increasingly recognised current biochemicaldiagnosis of AKI based on serum creatinine is inadequate not least because creatinine does not become abnormal until up to 48 hours after the onset of AKI. Hence there has been significant effort to identify reliable early markers of AKI. Biomarkers of AKI should improve trial design and outcome measures. AKI biomarkers may also improve the efficacy of agents designed to treat AKI since the drug can be given earlier in the disease course(11). Whilst AKI biomarkers are currently used in many trials, their application remains somewhat experimental with little standardisation.
Within the broad domains of AKI pathophysiology, there are multiple inter-related subcellular biomolecular pathways involving autocrine, paracrine and endocrine signalling. Interfering with one domain or pathway may result in secondary effects on others – the holy grail of AKI prevention is to find one drug target that is interlinked to many of these pathways and acts to prevent early cellular dysfunction in response to multiple insults (Figure 1). Drugs applied at a later stage will need to be concerned with limiting the ongoing acute cellular injury, reducing adverse inflammatory influx and beneficially promoting regeneration and repair. The molecular pathways targeted by the agents covered in this review are summarised in Figure 2.
A greater understanding of these issues and lessons learnt from previous failures has resulted in several agents now in clinical trial for AKI.
The purpose and focus of this review is to summarise the preclinical development and update on the progress of agents currently or recently in trial for AKI(Table 1). We designate some focus to reasons for recent failure of two agents and touch on new paradigms in pre-clinical targets for treatment of AKI.
2Agents in clinical trial for sterile AKI
2.1QPI-1002: p53 siRNA, Quark Pharmaceuticals
P53 is a transcription factor upregulated in response to multiple forms of cellular stress.P53 participates in severalstress-adaptive pathways including apoptosis, cell cycle arrest and senescence. More recently it has been discovered that beyond its role as a transcription factor it is a direct participant in necrotic cell death through formation of the mitochondrial permeability transition pore (MPTP); a key effector complex in hypoxic cell necrosis (12). QPI-1002 (also known as I5NP) is a “naked” synthetic siRNA that undergoes rapid renal excretion and is re-absorbed by and accumulates almost exclusively in the proximal tubular epithelial cell (PTEC)(13). QPI-1002 causes down regulation of p53 and loss of its function. Targeted deletion of p53 in the proximal tubules of mice produced significant benefits in IRI.The benefit was due to reduced necrosis, apoptosis and inflammation as well as reduced later fibrosis. Beneficial downstream signalling effects included reduced expression of poly[ADP-ribose] polymerase 1 (PARP-1) (another necrosis signalling molecule), and reduced phosphorylation of Smads(transforming growth factor beta (TGF-β) signal transduction molecules)(14). In rats, QPI-1002produced significant reductions in functional and histological kidney injury in both IRIand cisplatin nephrotoxicity (15).
In a phase 2b RCT for prophylaxis of DGF (NCT00802347), 331 kidney transplant recipients receiving deceased donor kidneys were administered QPI-1002 or placebo after graft reperfusion. Benefit was found in the expanded criteria donor group (n=177): patients receiving QPI-1002 exhibited numerically lower DGF rate (defined as need for dialysis within 7 days of transplant) (27.3 vs 39.3% p=0.11), fewer days on dialysis (13.4 vs 25.3 p=0.29) and a statistically significant better day-30 estimated glomerular filtration rate (eGFR) (34.8 vs 21.1 p=0.04) (16).
A phase 3 trial for prophylaxis of DGF in donation after brain stem death (DBD) kidneys is currently recruiting and will focus on donor age > 60 or predicted risk of DGF > 20% (NCT02610296). QPI-1002 has also completed phase 1 trial in patients at high risk of cardiac surgery-AKI (CS-AKI) (NCT00683553) with a phase 2 trial recruiting (NCT02610283).
2.2THR-184: Bone morphogenetic protein receptor agonist, Thrasos Therapeutics
Bone morphogenetic protein (BMP) receptors are ubiquitously expressed and belong to the TGF-β superfamilyinvolved in regulating inflammation and fibrosis.Increased BMP signalling has beneficial effects in acute and chronic kidney disease models (17-20) partly through antagonism of TGF-β signalling. BMP signalling produces benefit in these models mainlythrough BMP receptor phosphorylation ofreceptor regulated Smad1, 5 and 8 proteins. Smad proteins are direct transcriptional regulators; one of the most important targets may be inhibitor of differentiation (Id) proteins which promote cell proliferation (21). Smadproteins also signal through ERK, JNK and p38 MAP kinase pathways and BMP-7 activation is known to suppress cytokine expression, reduce apoptosis and promote renal regeneration in models of fibrosis and diabetic nephropathy (22-25). THR-184 is an agonist of the activin-like kinase 3 receptor (Alk3)(26) – Alk3 is the major BMP receptor expressed in tubular epithelial cells (27). The Alk3 receptor is significantly upregulated in PTECs in murine IRI whilst its ligand, BMP 7, is downregulated (19). THR-184showed significant benefit in mouse models of IRI, unilateral ureteric obstruction, nephrotoxic nephritis, Alport’s syndrome and diabetic nephropathy. Mechanism and site of action were demonstrated sincemice with PTEC specific deletion of Alk3 are not protected from IRI injury by THR-184 compared to wild-type control mice(26).
A phase 2b trial in 452 patients at high risk of CS-AKI has been completed (NCT01830920). A press release from Thrasos on 29/02/2016 stated that there was reduction in AKI rates according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria within 7 days of surgery in patients with CKD with the highest of the 4 doses tested (28). Thrasos stated they had only reached the “bottom of the therapeutic window” and aim to move rapidly into phase 3 trials with higher doses.
2.3BB-3: Hepatocyte growth factor-like molecule, AngionBiomedica Corp
The hepatocyte growth factor (HGF) receptor c-met, (a protein tyrosine kinase) is highly expressed in kidney and liver tissue (29). Both the receptor and ligand are upregulated in response to folic acid AKI in mice(30) and have pleiotropic functions. C-met activation is involved with regeneration and repair, suppression of tubular apoptosis, increased expression of survival proteins such as BCL-2(31) and suppression of cytokine generation by tubular epithelial cells (32). HGF has been shown to reduce kidney injury in several animal models.In IRI and cis-platin injury, c-met deletion significantly exacerbates injury and prevents the beneficial effects of HGF(33-37). BB-3 is a small molecule that potently activates the HGF receptor.
Recent experimental evidence has shown that BB-3 administered 24 hours after severe IRI in rats can improve creatinine levels, reduce tubular apoptosisand improve histological renal injury over the following 5 days. In the BB-3 group there was a 3-fold increase in tubular cellproliferation compared to vehicle 52 hours after severe IRI injury. Thus, it seems that BB-3 canpromote regeneration and repair of injured kidneys even when administered 24 hours after the injury (38).
In a phase 2b trial (NCT01286727)in renal transplant recipients, BB-3 was given within 36 hours of surgery only if there was evidence of delayed DGF (anuria/oliguria in the first 24 hours). In an interim analysis of 19 patients the most encouraging result was that the primary end-point (> 1.2L urine output per day by day 28) was met by 10/12 (83%) BB-3 treated patients vs 3/7 (43%) placebo-treated patients. This preliminary report also noted trends to less days on dialysis, lower serum creatinine and reduced length of stay with BB-3 treatment(39). A phase 3 study (NCT02474667)is now recruiting.
2.4Heme arginate: currently used in treatment of acute porphyria
Heme-oxygenase 1(HO-1) is an inducible cytosolic enzyme responsible for regulation of heme metabolism. Heme causes oxidative stress, inflammation and apoptosis and represents a crucial mechanism of injury in many forms of AKI (40). Pharmacological HO-1 induction and/or HO-1 gene manipulation has been shown to improve animal renal injury in cis-platin(41), IRI(42), lipopolysaccharide (LPS)(43) and transplant induced (44)renal injury models.HO-1can be induced by the drug heme arginate that is currently used in the treatment of acute porphryia.
In a proof of concept RCT in 37 renal transplant recipients, heme arginate given before and after cadaveric transplantation was associated with a significant increase in HO-1 protein levels in recipient peripheral blood mononuclear cells (PBMC) at days 1 and 3 and in a renal graft biopsy at day 5 (45) (NCT01286727). The trial was not powered to detect a difference in clinical outcomes. A phase 3 trial is planned.
2.5Ciclosporin A: CicloMulsion ® , Neurovie
Mitochondrial permeability transition pore(MPTP) formation is a key terminal event in hypoxic cell necrosis. This molecular complex forms a pore in the mitochondrial membrane resulting in mitochondrial, cell and organelle swelling followed by loss of cell membrane integrity. It has multiple potential positive regulators and activators. Ciclosporin A, (the calcineurin inhibitor used as an immunosuppressive agent)binds to cyclophilin D (CypD) (a positive regulatory component of MPTP) and reduces MPTP formation. In ischemic AKI, accumulation of reactive oxygen species (ROS)followed by the sudden re-oxygenation of energy deficient cells contributes to MPTP formation. MPTP formation may also be one of various terminal events in other interlinked intracellular death signaling pathways such as necroptosis, (see later)through the mixed lineage kinase like domain protein (MLKL) (46)and PARP-1 mediated cell death(47). Whilst the deletion of CypD protects against renal IRI in mice and administration of CypD inhibitors mimics this, there is evidence that other cell death pathways acting independently of MPTP contribute to renal IRI and that CypD is a positive regulator of, but not essential for MPTPformation(48, 49). Thus, CypD inhibition alone may not be sufficientsignificantly reduce AKI.Further understanding of MPTP formation and structure may uncover essential components of the MPTPthat may be pharmacologically targeted.
Ciclosporin A has been tested in a phase 2b RCT for reduction of AKI in cardiac surgery patients with CKD. Enrollment of 155 patients was concluded in May 2016 (NCT02397213). There is currently no data available for scrutiny.
3Agents in clinical trial for sepsis-associated AKI
The pathogenesis of sepsis associated AKI involves more potential drivers and processes than sterile AKI and is set on a complex background of systemic haemodynamic, microvascular and immune aberrations. Additional drivers of kidney injury in sepsis include systemic shock or hypotension, local microvascular dysfunction with relative renal hypoperfusion(even after correction of systemic shock), bacterial toxinswhich promote inflammation of the tubulointerstitium and have direct toxicity to renal tubules (e.g. LPS), direct effects of cytokine storm on renal cells and overactive immune cells(50). While agents in clinical trial for sepsis indications may impact on sepsis-associated renal failure, are few trials that specifically on renal outcomes.We will describe 3 with some focus on AKI.
3.1recAP: Recombinant human alkaline phosphatase, AM-Pharma
Recombinant human alkaline phosphatase (recAP)has benefits in septic AKI because of its ability to dephosphorylate and thus inactivate LPSand extracellular adenosine triphosphate (ATP). Whilst LPS is a potent toll-like receptor 4 (TLR-4) agonist, dephosphorylated LPS is an antagonist of TLR-4 (51).Extracellular ATP ischemotactic for neutrophils and a stimulator of the NLRP3inflammasome (a pathogen and damage associated molecular pattern receptor complex which drives cytokine production in AKI) (52). However, adenosine, (one of the dephosphorylated ATP products) has renoprotective effects (53). Therefore,recAP may not only reduce the systemic inflammatory response syndrome through reduced LPS burden during sepsis, but may also generate renoprotective by-products.
In a phase 2b trial with bovine alkaline phosphatase (AP) in intensive care unit (ICU) treated septic patients with AKI, AP significantly improved creatinine clearance at day 28, reduced urinary levels of Kidney Injury Molecule-1 (KIM-1) and Interleukin (IL) 18 and serum levels of C-reactive protein (CRP), LPS binding protein and IL-6 (NCT00511186)(54).A phase 2a trial with recAP was completed and phase 2b trial is now recruiting (NCT02182440).
3.2AB103: CD28 receptor blocker,Atox Bio
AB103 (originally p2TA) is a CD28 receptor mimetic that prevents binding of bacterial superantigensto the CD28 T-cell receptor. Inhibition of CD28 reduces cytokine storm (particularly tumour necrosis factor alpha, IL-2, 4, 6 and 10, interferon gamma and monocyte chemoattractant protein 1 (MCP-1) plasma levels),improves survival and ameliorates renal failure in mouse models of sepsis (55, 56). AB103underwent clinical trial for reduction in organ failure over 28 days in patients with necrotising soft tissue infections (NSTI)(57). Although not outlined specifically in the report of the original trial, data presented on the company website suggests that in the AB103 group 85% of patients with SA-AKI returned to within 50% of baseline creatinine within 7 days vs around 45% of patients that received placebo(58). Based on this, recovery from AKI in patients with NSTI has been included as a specific outcome in the phase 3 trialwhich is currently recruiting (NCT02469857).